Chapter 7 상염색체성 유전

* 상염색체성 유전 질환- 상동염색체상의 하나 혹은 두개 모두에 돌연변이에 의한 유전질환

* 성염색체성 유전 질환 - X 혹은 Y 염색체상의 돌연변이

7.1 상염색체성 단일 유전자 유전

- 상염색체성 유전자는 쌍으로 존재 그 중 하나는 부친, 다른 하나는 모친으로부터 받은 것임

- 쌍으로 존재하는 유전자가 서로 다른 형태로 존재할 때 대립인자라고함. 대립인자는 돌연변이에 의해 생길 수 있으며, 기능이 변할 수 도 있다.

- homozygous : 두 유전자가 동일한 형태일 때

- heterozygous : 두 유전자가 서로 다른 형태일 때

- trait : 유전자에 의해 결전된 특징

- dominant : heterozygote에서 그 형질이 나타날 때 그 형질을 말함

- recessive : homozygote 일때만 나타나는 형질을 말함

- codominant : heterozygote 일 때 두 형질 모두 나타나는 형질을 말함

7.2 상 염색체성 우성 유전

- 예) 가족성콜레스테롤과잉혈증(FH: 황색종(xanthomata), 관상동맥질환 발생) 환자의 가계도:

* 남녀 모두 같은 비율로 질병이 걸림

* 각 세대에 환자가 나타남

* 남성 환자는 남녀 모두에게 전파하고 여성 환자도 마찬가지

* 정상인은 질병을 유전시키지 않음

* 19번 염색체의 p-arm에 있는 단일 유전자에 돌연변이

* 가족중 각 환자는 heterozygote

- 환자인 부모로부터 돌연변이 유전자를 받을 확률: Fig. 7.4

- 동일한 돌연변이 유전자를 갖고 있더라도 발병시기, 병의 증상의 정도 등이 다를 수 있다.

- FH 유전자의 돌연변이:

* 200 가지 돌연변이가 LDL receptor 유전자에 존재

* LDL receptor : LDL을 세포내로 이동 이 유전자가 고장나면 cholesterol을 포함하는 LDL 의 혈 중 농도가 증가

* homozygous인 환자 : 어린시절에 발병하여 죽음

* 혈장중 지질농도를 측정하여 가족 중 환자 추적

- 상 염색체성 우성유전은 열성유전보다 증상이 덜한 경향이 있다.

- 열성유전의 경우 효소유전자가 파괴되는 경우가 흔하며, 반면에 우성유전의 경우는 구조단백질, 운반체, 수용체 등에 돌연변이가 된 경우가 흔함

- 어떤 우성유전의 경우, 예) 대장암, 돌연변이 유전자를 갖고 있더라도 정상적인 표현형을 갖는 경우가 있다. 이러한 현상을 non-penetrance 라고 한다. 따라서 세대를 띠어 넘어서 나타날 수 있다.

- 또 어떤 경우, 예) Huntington disease, 증상이 나타나는 것이 나이에 의존하여, 발병나이 이전에는 진단이 안된다

- penetrance 가 완전한 질환일 경우 환자를 가진 정상부모가 다시 환자를 낳을 확률은 낮다. 그러나 gonadal mosoicism일 경우는 예외로서 정상인 부모가 또다시 환자인 자식을 놓는다.

- 돌연변이 유전자가 unstable한 경우도 있다. 예) Myotonic dystropy(이영양성근긴장증)은 성인성 근육위축증으로서 불안한 길이돌연변이로 인한 것이다. 세대가 거듭하면서 증폭되며, 증폭정도에 따라서 증세가 심해짐

- 자식을 못볼정도로 심각한 우성유전도 있다. 아페르 증후군(첨두합지증), 진행성 화골염: 부모는 정상이며, 아이는 새로운 돌연변이임.
- 부친의 나이에 따라 증가하는 유전병: 마르팡 증후군, achondroplasia(연골발육부전증),

- 망막아세포종, 신경섬유종: 부친에서 새 돌연변이 생성으로 유전

Learning About Familial Hypercholesterolemia

What is familial hypercholesterolemia?

What are the symptoms of familial hypercholesterolemia?

How is familial hypercholesterolemia diagnosed?

What is the treatment for familial hypercholesterolemia?

Is familial hypercholesterolemia inherited?

NHGRI Clinical Research on Familial Hypercholesterolemia

Additional Resources About Familial Hypercholesterolemia

What is familial hypercholesterolemia?

Familial hypercholesterolemia is an inherited condition that causes high levels of LDL (low density lipoprotein) cholesterol levels beginning at birth, and heart attacks at an early age. Cholesterol is a fat-like substance that is found in the cells of the body. Cholesterol is also found in some foods. The body needs some cholesterol to work properly and uses cholesterol to make hormones, vitamin D, and substances that help with food digestion. However, if too much cholesterol is present in the blood stream, it builds up in the wall of the arteries and increases the risk of heart disease.

Cholesterol is carried in the blood stream in small packages called lipoproteins. These small packages are made up of fat (lipid) on the inside and proteins on the outside. There are two main kinds of lipoprotein that carry cholesterol throughout the body. These are: low density lipoprotein (LDL) and high density lipoprotein (HDL).

The cholesterol carried by LDL is some times called the "bad cholesterol." People who have familial hypercholesterolemia have high levels of LDL cholesterol because they can not remove the LDL from the blood stream properly. The organ responsible for the removal of the LDL is the liver. High levels of LDL cholesterol in the blood increase the risk for heart attacks and heart disease.

The cholesterol carried by HDL is sometimes called the "good cholesterol." HDL carries cholesterol from other parts of the body to the liver. The liver removes cholesterol from the body. Higher levels of HDL cholesterol lower a person's chance for getting heart disease.

Men who have familial hypercholesterolemia have heart attacks in their 40's to 50's, and 85 percent of men with the disorder have a heart attack by age 60. Women who have familial hypercholesterolemia also have an increased risk for heart attack, but it happens 10 years later than in men (so in their 50's and 60's).

Familial hypercholesterolemia is inherited in families in an autosomal dominant manner. In autosomal dominant inherited conditions, a parent who carries an altered gene that causes the condition has a 1 in 2 (50 percent) chance to pass on that altered gene to each of his or her children.

The altered gene (gene mutation) that causes familial hypercholesterolemia is located on chromosome number 19. It contains the information for a protein called LDL receptor that is responsible to clear up LDL from the blood stream. One in 500 individuals carries one altered gene causing familial hypercholesterolemia. These individuals are called heterozygotes. More rarely, a person inherits the gene mutation from both parents, making them genetically homozygous. Individuals who are homozygous have a much more severe form of hypercholesterolemia, with heart attack and death often occurring before age 30.

What are the symptoms of familial hypercholesterolemia?

The major symptoms and signs of familial hypercholesterolemia are:

High levels of total cholesterol and LDL cholesterol.

A strong family history of high levels of total and LDL cholesterol and/or early heart attack.

Elevated and therapy-resistant levels of LDL in either or both parents.

Xanthomas (waxy deposits of cholesterol in the skin or tendons).

Xanthelasmas (cholesterol deposits in the eyelids).

Corneal arcus (cholesterol deposit around the cornea of the eye).

If angina (chest pain) is present, it may be sign that heart disease is present.

Individuals who have homozygous familial hypercholesterolemia develop xanthomas beneath the skin over their elbows, knees and buttocks as well as in the tendons at a very early age, sometime in infancy. Heart attacks and death may occur before 30.

How is familial hypercholesterolemia diagnosed?

Diagnosis of familial hypercholesterolemia is based on physical examination and laboratory testing. Physical examination may find xanthomas and xanthelasmas (skin lesions caused by cholesterol rich lipoprotein deposits), and cholesterol deposits in the eye called corneal arcus.

Laboratory testing includes blood testing of cholesterol levels, studies of heart function, and genetic testing. Blood testing of cholesterol levels may show: increased total cholesterol usually above 300 mg/dl (total cholesterol of more than 250 mg/dl in children) and LDL levels usually above 200 mg/dl. Studies of heart function, such as a stress test, may be abnormal. Genetic testing may show an alteration (mutation) in the LDL receptor gene.

What is the treatment for familial hypercholesterolemia?

The overall goal of treatment is to lower the risk for atherosclerotic heart disease by lowering the LDL cholesterol levels in the blood stream. Atherosclerosis is a condition in which fatty material collects along the walls of arteries. This fatty material thickens, hardens, and may eventually block the arteries. Atherosclerosis happens when fat and cholesterol and other substances build up in the arteries and form a hardened material called plaque. The plaque deposits make the arteries less flexible and more difficult for blood to flow leading to heart attack and stroke.

The first step in treatment for an individual who has heterozygous familial hypercholesterolemia is changing the diet to reduce the total amount of fat eaten to 30 percent of the total daily calories. This can be done by limiting the amount of beef, pork, and lamb in the diet; cutting out butter, whole milk and fatty cheeses as well as some oils like coconut and palm oils; and eliminating egg yolks, organ meats and other sources of saturated fat from animals. Dietary counseling is often recommended to help people to make these changes in their eating habits.

Exercise, especially to lose weight, may also help in lowering cholesterol levels.

Drug therapy is usually necessary in combination with diet, weight loss, and exercise, as these interventions may not be able to lower cholesterol levels alone. There are a number of cholesterol-lowering medications that are currently used. The first and more effective choice are drugs called "statins." Other drugs that may be used in combination with or instead of the statins are: bile acid sequestrant resins (for example, cholestyramine), ezetemibe, nicotinic acid (niacin), gemfibrozil, and fenofibrate.

Individuals who have homozygous familial hypercholesterolemia need more aggressive therapies to treat their significantly elevated levels of cholesterol. Often drug therapies are not sufficient to lower LDL cholesterol levels at the desiderated goal and these individuals may require periodical LDL apheresis, a procedure to "clean up" LDL from the blood stream, or highly invasive surgery such as a liver transplant.

Is familial hypercholesterolemia inherited?

Familial hypercholesterolemia is inherited in an autosomal dominant manner. This means that to have this condition, it is sufficient that the altered (mutated) gene is present on only one of the person's two number 19 chromosomes. A person who inherits one copy of the gene mutation causing familial hypercholesterolemia from one of his/her parents is said to have heterozygous familial hypercholesterolemia. This person has a 1 in 2 (50 percent) chance to pass on the mutated gene to each of his/her children.

A person who inherits a mutated copy of the gene causing familial hypercholesterolemia from both parents is said to have homozygous familial hypercholesterolemia. This is a much more severe form of familial hypercholesterolemia than heterozygous familial hypercholesterolemia. Each of this person's children will inherit one copy of the mutated gene and will have heterozygous familial hypercholesterolemia

출처: http://www.genome.gov/25520184

Xanthoma

From Wikipedia, the free encyclopedia

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See also: Xanthelasma

Xanthoma
Classification and external resources
Photograph of patient's hands showing multiple xanthoma tendinosum. Kumar et al. Cases Journal 2008
ICD-10	E78.2 (ILDS E78.280), K13.4
ICD-9	272.2
DiseasesDB	28524
MedlinePlus	001447
eMedicine	derm/461
MeSH	D014973

A xanthoma (pl. xanthomas or xanthomata) (condition: xanthomatosis), from Greek xanthos, ξανθος, "yellow", is a deposition of yellowish cholesterol-rich material in tendons or other body parts in various disease states.[1] They are cutaneous manifestations of lipidosis in which there is an accumulation of lipids in large foam cells within the skin.[1]

They are associated with hyperlipidemias, both primary and secondary types.

Tendon xanthomas are associated with Type II hyperlipidemia, chronic biliary tract obstruction, and primary biliary cirrhosis.

Palmar xanthomata and tuboeruptive xanthomata (over knees and elbows) occur in Type III hyperlipidaemia

출처: http://en.wikipedia.org/wiki/Xanthoma

7.3 상염색체성 열성유전

-예) 낫세포빈혈증

* 만성 악성빈혈

* 적혈구 구조이상으로 혈관 경색

* 정상성인의 주된 hemoglobin 은 HbA로서 두개의 alpha, 두개의 beta 사슬로 됨

* 11번 염색체의 beta-globin 유전자(Hb B)에 돌연변이로 Hb S 유전자로 변이

* 적혈구 모양이상, 산소운반능력 감소

* 환자는 두개의 Hb S genes을 갖고 있으며(Hb S/Hb S), HbS(두개의 alpha 사슬과 두 개의 돌연변이 된 beta 사슬로 됨)를 갖게 됨

* carrier(Hb B/Bb S) 는 임상적으로 정상: carrier는 단백질의 전기영동으로 확인가능(Fig.	7.6)

* 보인자 양친의 경우 자식의 발병확률: Fig. 7.8

Hemoglobin

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Haemoglobin, human, adult (heterotetramer, (αβ)2)
Structure of human hemoglobin. The proteins' α and β subunits are in red and blue, and the iron-containing heme groups in green. From PDB 1GZX Proteopedia Hemoglobin
-
Protein type		metalloprotein, globulin
Function		oxygen-transport
Cofactor(s)		heme (4)
-
Subunit Name	Gene	Chromosomal Locus
Hb-α1	HBA1	Chr. 16 p13.3
Hb-α2	HBA2	Chr. 16 p13.3
Hb-β	HBB	Chr. 11 p15.5

Hemoglobin (pron.: /hiːməˈɡloʊbɪn/; also spelled haemoglobin and abbreviated Hb or Hgb) is the iron-containing oxygen-transport metalloprotein in the red blood cells of all vertebrates[1] (with the exception of the fish family Channichthyidae[2]) as well as the tissues of some invertebrates. Hemoglobin in the blood carries oxygen from the respiratory organs (lungs or gills) to the rest of the body (i.e. the tissues) where it releases the oxygen to burn nutrients to provide energy to power the functions of the organism, and collects the resultant carbon dioxide to bring it back to the respiratory organs to be dispensed from the organism.

In mammals, the protein makes up about 97% of the red blood cells' dry content, and around 35% of the total content (including water).[3] Hemoglobin has an oxygen binding capacity of 1.34 mL O2 per gram of hemoglobin,[4] which increases the total blood oxygen capacity seventy-fold compared to dissolved oxygen in blood. The mammalian hemoglobin molecule can bind (carry) up to four oxygen molecules.[5]

Hemoglobin is involved in the transport of other gases: it carries some of the body's respiratory carbon dioxide (about 10% of the total) as carbaminohemoglobin, in which CO2 is bound to the globin protein. The molecule also carries the important regulatory molecule nitric oxide bound to a globin protein thiol group, releasing it at the same time as oxygen.[6]

Hemoglobin is also found outside red blood cells and their progenitor lines. Other cells that contain hemoglobin include the A9 dopaminergic neurons in the substantia nigra, macrophages, alveolar cells, and mesangial cells in the kidney. In these tissues, hemoglobin has a non-oxygen-carrying function as an antioxidant and a regulator of iron metabolism.[7]

Hemoglobin and hemoglobin-like molecules are also found in many invertebrates, fungi, and plants. In these organisms, hemoglobins may carry oxygen, or they may act to transport and regulate other things such as carbon dioxide, nitric oxide, hydrogen sulfide and sulfide. A variant of the molecule, called leghemoglobin, is used to scavenge oxygen away from anaerobic systems, such as the nitrogen-fixing nodules of leguminous plants, before the oxygen can poison the system.

Contents

1 Research history

2 Genetics

3 Synthesis

4 Structure

4.1 Oxygen saturation

4.1.1 Oxyhemoglobin

4.1.2 Deoxygenated hemoglobin

5 Iron's oxidation state in oxyhemoglobin

6 Binding for ligands other than oxygen

6.1 Cooperative

6.2 Competitive

6.3 Allosteric

7 Types in humans

8 Degradation in vertebrate animals

9 Role in disease

10 Diagnostic uses

11 Analogues in non-vertebrate organisms

12 Other oxygen-binding proteins

13 Presence in nonerythroid cells

14 In history, art and music

15 See also

16 References

17 Further reading

18 External links

Research history

In 1825 J.F. Engelhard[8] discovered that the ratio of iron to protein is identical in the hemoglobins of several species. From the known atomic mass of iron he calculated the molecular mass of hemoglobin to n × 16000 (n = number of irons per hemoglobin, now known to be 4), the first determination of a protein's molecular mass. This "hasty conclusion" drew a lot of ridicule at the time from scientists who could not believe that any molecule could be that big. Adair confirmed Engelhard's results in 1925 by measuring the osmotic pressure of hemoglobin solutions.[9]

The oxygen-carrying protein hemoglobin was discovered by Hünefeld in 1840.[10] In 1851,[11] Otto Funke published a series of articles in which he described growing hemoglobin crystals by successively diluting red blood cells with a solvent such as pure water, alcohol or ether, followed by slow evaporation of the solvent from the resulting protein solution.[12] Hemoglobin's reversible oxygenation was described a few years later by Felix Hoppe-Seyler.[13]

In 1959 Max Perutz determined the molecular structure of myoglobin(similar to hemoglobin) by X-ray crystallography.[14][15] This work resulted in his sharing with John Kendrew the 1962 Nobel Prize in Chemistry.

The role of hemoglobin in the blood was elucidated by physiologist Claude Bernard. The name hemoglobin is derived from the words heme and globin, reflecting the fact that each subunit of hemoglobin is a globular protein with an embedded heme group. Each heme group contains one iron atom, that can bind one oxygen molecule through ion-induced dipole forces. The most common type of hemoglobin in mammals contains four such subunits.

Genetics

Hemoglobin consists mostly of protein subunits (the "globin" chains), and these proteins, in turn, are folded chains of a large number of different amino acids called polypeptides. The amino acid sequence of any polypeptide created by a cell is in turn determined by the stretches of DNA called genes. In all proteins, it is the amino acid sequence which determines the protein's chemical properties and function.

There is more than one hemoglobin gene. The amino acid sequences of the globin proteins in hemoglobins usually differ between species. These differences grow with evolutionary distance between species. For example, the most common hemoglobin sequences in humans and chimpanzees are nearly identical, differing by only one amino acid in both the alpha and the beta globin protein chains. These differences grow larger between less closely related species.

Even within a species, different variants of hemoglobin always exist, although one sequence is usually a "most common" one in each species. Mutations in the genes for the hemoglobin protein in a species result in hemoglobin variants.[16][17] Many of these mutant forms of hemoglobin cause no disease. Some of these mutant forms of hemoglobin, however, cause a group of hereditary diseases termed the hemoglobinopathies. The best known hemoglobinopathy is sickle-cell disease, which was the first human disease whose mechanism was understood at the molecular level. A (mostly) separate set of diseases called thalassemias involves underproduction of normal and sometimes abnormal hemoglobins, through problems and mutations in globin gene regulation. All these diseases produce anemia.[18]

Variations in hemoglobin amino acid sequences, as with other proteins, may be adaptive. For example, recent studies have suggested genetic variants in deer mice that help explain how deer mice that live in the mountains are able to survive in the thin air that accompanies high altitudes. A researcher from the University of Nebraska-Lincoln found mutations in four different genes that can account for differences between deer mice that live in lowland prairies versus the mountains. After examining wild mice captured from both highlands and lowlands, it was found that: the genes of the two breeds are "virtually identical–except for those that govern the oxygen-carrying capacity of their hemoglobin". "The genetic difference enables highland mice to make more efficient use of their oxygen", since less is available at higher altitudes, such as those in the mountains.[19] Mammoth hemoglobin featured mutations that allowed for oxygen delivery at lower temperatures, thus enabling mammoths to migrate to higher latitudes during the Pleistocene.[20]

Synthesis

Hemoglobin (Hb) is synthesized in a complex series of steps. The heme part is synthesized in a series of steps in the mitochondria and the cytosol of immature red blood cells, while the globin protein parts are synthesized by ribosomes in the cytosol.[21] Production of Hb continues in the cell throughout its early development from the proerythroblast to the reticulocyte in the bone marrow. At this point, the nucleus is lost in mammalian red blood cells, but not in birds and many other species. Even after the loss of the nucleus in mammals, residual ribosomal RNA allows further synthesis of Hb until the reticulocyte loses its RNA soon after entering the vasculature (this hemoglobin-synthetic RNA in fact gives the reticulocyte its reticulated appearance and name).

Structure

Heme  group

Hemoglobin has a quaternary structure characteristic of many multi-subunit globular proteins.[22] Most of the amino acids in hemoglobin form alpha helixes, connected by short non-helical segments. Hydrogen bonds stabilize the helical sections inside this protein, causing attractions within the molecule, folding each polypeptide chain into a specific shape.[23] Hemoglobin's quaternary structure comes from its four subunits in roughly a tetrahedral arrangement.[22]

In most vertebrates, the hemoglobin molecule is an assembly of four globular protein subunits. Each subunit is composed of a protein chain tightly associated with a non-protein heme group. Each protein chain arranges into a set of alpha-helix structural segments connected together in a globin fold arrangement, so called because this arrangement is the same folding motif used in other heme/globin proteins such as myoglobin.[24][25] This folding pattern contains a pocket that strongly binds the heme group.

A heme group consists of an iron (Fe) ion (charged atom) held in a heterocyclic ring, known as a porphyrin. This porphyrin ring consists of four pyrrole molecules cyclically linked together (by methene bridges) with the iron ion bound in the center.[26] The iron ion, which is the site of oxygen binding, coordinates with the four nitrogens in the center of the ring, which all lie in one plane. The iron is bound strongly (covalently) to the globular protein via the imidazole ring of F8 histidine residue (also known as the proximal histidine) below the porphyrin ring. A sixth position can reversibly bind oxygen by a coordinate covalent bond,[27] completing the octahedral group of six ligands. Oxygen binds in an "end-on bent" geometry where one oxygen atom binds Fe and the other protrudes at an angle. When oxygen is not bound, a very weakly bonded water molecule fills the site, forming a distorted octahedron.

Even though carbon dioxide is carried by hemoglobin, it does not compete with oxygen for the iron-binding positions, but is actually bound to the protein chains of the structure.

The iron ion may be either in the Fe2+ or in the Fe3+ state, but ferrihemoglobin (methemoglobin) (Fe3+) cannot bind oxygen.[28] In binding, oxygen temporarily and reversibly oxidizes (Fe2+) to (Fe3+) while oxygen temporarily turns into superoxide, thus iron must exist in the +2 oxidation state to bind oxygen. If superoxide ion associated to Fe3+ is protonated the hemoglobin iron will remain oxidized and incapable of binding oxygen. In such cases, the enzyme methemoglobin reductase will be able to eventually reactivate methemoglobin by reducing the iron center.

In adult humans, the most common hemoglobin type is a tetramer (which contains 4 subunit proteins) called hemoglobin A, consisting of two α and two β subunits non-covalently bound, each made of 141 and 146 amino acid residues, respectively. This is denoted as α2β2. The subunits are structurally similar and about the same size. Each subunit has a molecular weight of about 17,000 daltons[citation needed], for a total molecular weight of the tetramer of about 64,000 daltons (64,458 g/mol).[29] Thus, 1 g/dL = 0.1551 mmol/L. Hemoglobin A is the most intensively studied of the hemoglobin molecules.

In human infants, the hemoglobin molecule is made up of 2 α chains and 2 γ chains. The gamma chains are gradually replaced by β chains as the infant grows.[30]

The four polypeptide chains are bound to each other by salt bridges, hydrogen bonds, and the hydrophobic effect.

Oxygen saturation

In general, hemoglobin can be saturated with oxygen molecules (oxyhemoglobin), or desaturated with oxygen molecules (deoxyhemoglobin).[31]

Oxyhemoglobin

Oxyhemoglobin is formed during physiological respiration when oxygen binds to the heme component of the protein hemoglobin in red blood cells. This process occurs in the pulmonary capillaries adjacent to the alveoli of the lungs. The oxygen then travels through the blood stream to be dropped off at cells where it is utilized as a terminal electron acceptor in the production of ATP by the process of oxidative phosphorylation. It does not, however, help to counteract a decrease in blood pH. Ventilation, or breathing, may reverse this condition by removal of carbon dioxide, thus causing a shift up in pH.[32]

Hemoglobin exists in two forms, a taut (tense) form (T) and a relaxed form (R). Various factors such as low pH, high CO2 and high 2,3 BPG at the level of the tissues favor the taut form, which has low oxygen affinity and releases oxygen in the tissues. Conversely, a high pH, low CO2, or low 2,3 BPG favors the relaxed form which can better bind oxygen.[33] The partial pressure of the system also affects O2 affinity where, at high partial pressures of oxygen (such as those present in the alveoli), the relaxed (high affinity, R) state is favoured. Inversely, at low partial pressures (such as those present in respiring tissues) , the (low affinity, T) tense state is favoured.[34] Additionally, the binding of oxygen to the Iron-II heme pulls the iron into the plane of the porphryn ring, causing a slight conformational shift. The shift encourages oxygen to bind to the three remaining hemes within hemoglobin (thus, oxygen binding is cooperative).

Deoxygenated hemoglobin

Deoxygenated hemoglobin is the form of hemoglobin without the bound oxygen. The absorption spectra of oxyhemoglobin and deoxyhemoglobin differ. The oxyhemoglobin has significantly lower absorption of the 660 nm wavelength than deoxyhemoglobin, while at 940 nm its absorption is slightly higher. This difference is used for measurement of the amount of oxygen in patient's blood by an instrument called pulse oximeter. This difference also accounts for the presentation of cyanosis, the blue to purplish color that tissues develop during hypoxia.

Iron's oxidation state in oxyhemoglobin

Assigning oxygenated hemoglobin's oxidation state is difficult because oxyhemoglobin (Hb-O2), by experimental measurement, is diamagnetic (no net unpaired electrons), yet the low-energy electron configurations in both oxygen and iron are paramagnetic (suggesting at least one unpaired electron in the complex). The lowest-energy form of oxygen, and the lowest energy forms of the relevant oxidation states of iron, are these:

Triplet oxygen, the lowest energy molecular oxygen species, has two unpaired electrons in antibonding π* molecular orbitals.

Iron(II) tends to exist in a high-spin configuration where unpaired electrons exist in Eg antibonding orbitals.

Iron(III) has an odd number of electrons, and thus must have one or more unpaired electrons, in any energy state.

All of these structures are paramagnetic (have unpaired electrons), not diamagnetic. Thus, a non-intuitive (e.g., a higher-energy for at least one species) distribution of electrons in the combination of iron and oxygen must exist, in order to explain the observed diamagnetism and no unpaired electrons.

The three logical possibilities to produce diamagnetic (no net spin) Hb-O2 are:

Low-spin Fe2+ binds to singlet oxygen. Both low-spin iron and singlet oxygen are diamagnetic. However, the singlet form of oxygen is the higher-energy form of the molecule.

Low-spin Fe3+ binds to .O2- (the superoxide ion) and the two unpaired electrons couple antiferromagnetically, giving diamagnetic properties.

Low-spin Fe4+ binds to peroxide, O22-. Both are diamagnetic.

Direct experimental data:

X-ray photoelectron spectroscopy suggests iron has an oxidation state of approximately 3.2

infrared stretching frequencies of the O-O bond suggests a bond length fitting with superoxide (a bond order of about 1.6, with superoxide being 1.5).

X-ray Absorption Near Edge Structures at the iron K-edge. The energy shift of 5 eV between Deoxyhemoglobin and Oxyhemoglobin, as for all the Methemoglobin species, strongly suggests an actual local charge closer to Fe3+ than Fe2+.[35][36][37]

Thus, the nearest formal oxidation state of iron in Hb-O2 is the +3 state, with oxygen in the -1 state (as superoxide .O2-). The diamagnetism in this configuration arises from the single unpaired electron on superoxide aligning antiferromagnetically from the single unpaired electron on iron, to give no net spin to the entire configuration, in accordance with diamagnetic oxyhemoglobin from experiment.[38][39]

The second choice of the three logical possibilities above for diamagnetic oxyhemoglobin being found correct by experiment, is not surprising: singlet oxygen (possibility #1) and large separations of charge (possibility #3) are both unfavorably high-energy states. Iron's shift to a higher oxidation state in Hb-O2 decreases the atom's size, and allows it into the plane of the porphyrin ring, pulling on the coordinated histidine residue and initiating the allosteric changes seen in the globulins.

Early postulates by bio-inorganic chemists claimed that possibility #1 (above) was correct and that iron should exist in oxidation state II. This seemed particularly likely since the iron oxidation state III as methemoglobin, when not accompanied by superoxide .O2- to "hold" the oxidation electron, was known to render hemoglobin incapable of binding normal triplet O2 as it occurs in the air. It was thus assumed that iron remained as Fe(II) when oxygen gas was bound in the lungs. The iron chemistry in this previous classical model was elegant, but the required presence of the required diamagnetic high-energy singlet oxygen was never explained. It was classically argued that the binding of an oxygen molecule placed high-spin iron(II) in an octahedral field of strong-field ligands; this change in field would increase the crystal field splitting energy, causing iron's electrons to pair into the low-spin configuration, which would be diamagnetic in Fe(II). This forced low-spin pairing is indeed thought to happen in iron when oxygen binds, but is not enough to explain iron's change in size. Extraction of an additional electron from iron by oxygen is required to explain both iron's smaller size and observed increased oxidation state, and oxygen's weaker bond.

It should be noted that the assignment of a whole-number oxidation state is a formalism, as the covalent bonds are not required to have perfect bond orders involving whole electron transfer. Thus, all three models for paramagnetic Hb-O2 may contribute to some small degree (by resonance) to the actual electronic configuration of Hb-O2. However, the model of iron in Hb-O2 being Fe(III) is more correct than the classical idea that it remains Fe(II).

Binding for ligands other than oxygen

Besides the oxygen ligand, which binds to hemoglobin in a cooperative manner, hemoglobin ligands also include competitive inhibitors such as carbon monoxide (CO) and allosteric ligands such as carbon dioxide (CO2) and nitric oxide (NO). The carbon dioxide is bound to amino groups of the globin proteins as carbaminohemoglobin, and is thought to account for about 10% of carbon dioxide transport in mammals. Nitric oxide is bound to specific thiol groups in the globin protein to form an S-nitrosothiol which dissociates into free nitric oxide and thiol again, as the hemoglobin releases oxygen from its heme site. This nitric oxide transport to peripheral tissues is hypothesized to assist oxygen transport in tissues, by releasing vasodilatory nitric oxide to tissues in which oxygen levels are low.[40]

Cooperative

A schematic visual model of oxygen-binding process, showing all four monomers and hemes, and protein chains only as diagramatic coils, to facilitate visualization into the molecule. Oxygen is not shown in this model, but, for each of the iron atoms, it binds to the iron (red sphere) in the flat heme. For example, in the upper left of the four hemes shown, oxygen binds at the left of the iron atom shown in the upper left of diagram. This causes the iron atom to move backward into the heme which holds it (the iron moves upward as it binds oxygen, in this illustration), tugging the histidine residue (modeled as a red pentagon on the right of the iron) closer, as it does. This, in turn, pulls on the protein chain holding the histidine.

When oxygen binds to the iron complex, it causes the iron atom to move back toward the center of the plane of the porphyrin ring (see moving diagram). At the same time, the imidazole side-chain of the histidine residue interacting at the other pole of the iron is pulled toward the porphyrin ring. This interaction forces the plane of the ring sideways toward the outside of the tetramer, and also induces a strain in the protein helix containing the histidine as it moves nearer to the iron atom. This strain is transmitted to the remaining three monomers in the tetramer, where it induces a similar conformational change in the other heme sites such that binding of oxygen to these sites becomes easier.

In the tetrameric form of normal adult hemoglobin, the binding of oxygen is, thus, a cooperative process. The binding affinity of hemoglobin for oxygen is increased by the oxygen saturation of the molecule, with the first oxygens bound influencing the shape of the binding sites for the next oxygens, in a way favorable for binding. This positive cooperative binding is achieved through steric conformational changes of the hemoglobin protein complex as discussed above; i.e., when one subunit protein in hemoglobin becomes oxygenated, a conformational or structural change in the whole complex is initiated, causing the other subunits to gain an increased affinity for oxygen. As a consequence, the oxygen binding curve of hemoglobin is sigmoidal, or S-shaped, as opposed to the normal hyperbolic curve associated with noncooperative binding.

The dynamic mechanism of the cooperativity in hemoglobin and its relation with the low-frequency resonance has been discussed.[41]

Competitive

The binding of oxygen is affected by molecules such as carbon monoxide (CO) (for example, from tobacco smoking, car exhaust, and incomplete combustion in furnaces). CO competes with oxygen at the heme binding site. Hemoglobin binding affinity for CO is 250 times greater than its affinity for oxygen,[42] meaning that small amounts of CO dramatically reduce hemoglobin's ability to transport oxygen. Since carbon monoxide is a colorless, odorless and tasteless gas, and poses a potentially fatal threat, detectors have become commercially available to warn of dangerous levels in residences. When hemoglobin combines with CO, it forms a very bright red compound called carboxyhemoglobin, which may cause the skin of CO poisoning victims to appear pink in death, instead of white or blue. When inspired air contains CO levels as low as 0.02%, headache and nausea occur; if the CO concentration is increased to 0.1%, unconsciousness will follow. In heavy smokers, up to 20% of the oxygen-active sites can be blocked by CO.

In similar fashion, hemoglobin also has competitive binding affinity for cyanide (CN-), sulfur monoxide (SO), nitric oxide (NO), and sulfide (S2-), including hydrogen sulfide (H2S). All of these bind to iron in heme without changing its oxidation state, but they nevertheless inhibit oxygen-binding, causing grave toxicity.

The iron atom in the heme group must initially be in the ferrous (Fe2+) oxidation state to support oxygen and other gases' binding and transport (it temporarily switches to ferric during the time oxygen is bound, as explained above). Initial oxidation to the ferric (Fe3+) state without oxygen converts hemoglobin into "hemiglobin" or methemoglobin (pronounced "MET-hemoglobin"), which cannot bind oxygen. Hemoglobin in normal red blood cells is protected by a reduction system to keep this from happening. Nitric oxide is capable of converting a small fraction of hemoglobin to methemoglobin in red blood cells. The latter reaction is a remnant activity of the more ancient nitric oxide dioxygenase function of globins.

Allosteric

Further information: Oxygen-hemoglobin dissociation curve

Carbon dioxide occupies a different binding site on the hemoglobin. Carbon dioxide is more readily dissolved in deoxygenated blood, facilitating its removal from the body after the oxygen has been released to tissues undergoing metabolism. This increased affinity for carbon dioxide by the venous blood is known as the Haldane effect. Through the enzyme carbonic anhydrase, carbon dioxide reacts with water to give carbonic acid, which decomposes into bicarbonate and protons:

CO2 + H2O → H2CO3 → HCO3- + H+

The sigmoidal shape of hemoglobin's oxygen-dissociation curve results from cooperative binding of oxygen to hemoglobin.

Hence blood with high carbon dioxide levels is also lower in pH (more acidic). Hemoglobin can bind protons and carbon dioxide, which causes a conformational change in the protein and facilitates the release of oxygen. Protons bind at various places on the protein, while carbon dioxide binds at the α-amino group.[43] Carbon dioxide binds to hemoglobin and forms carbaminohemoglobin.[44] This decrease in hemoglobin's affinity for oxygen by the binding of carbon dioxide and acid is known as the Bohr effect (shifts the O2-saturation curve to the right). Conversely, when the carbon dioxide levels in the blood decrease (i.e., in the lung capillaries), carbon dioxide and protons are released from hemoglobin, increasing the oxygen affinity of the protein. A reduction in the total binding capacity of hemoglobin to oxygen (i.e. shifting the curve down, not just to the right) due to reduced pH is called the root effect. This is seen in bony fish.

It is necessary for hemoglobin to release the oxygen that it binds; if not, there is no point in binding it. The sigmoidal curve of hemoglobin makes it efficient in binding (taking up O2 in lungs), and efficient in unloading (unloading O2 in tissues).[45]

In people acclimated to high altitudes, the concentration of 2,3-Bisphosphoglycerate (2,3-BPG) in the blood is increased, which allows these individuals to deliver a larger amount of oxygen to tissues under conditions of lower oxygen tension. This phenomenon, where molecule Y affects the binding of molecule X to a transport molecule Z, is called a heterotropic allosteric effect.

Animals other than humans use different molecules to bind to hemoglobin and change its O2 affinity under unfavorable conditions. Fish use both ATP and GTP. These bind to a phosphate "pocket" on the fish hemoglobin molecule, which stabilizes the tense state and therefore decreases oxygen affinity.[46] GTP reduces hemoglobin oxygen affinity much more than ATP, which is thought to be due to an extra hydrogen bond formed that further stabilizes the tense state.[47] Under hypoxic conditions, the concentration of both ATP and GTP is reduced in fish red blood cells to increase oxygen affinity.[48]

A variant hemoglobin, called fetal hemoglobin (HbF, α2γ2), is found in the developing fetus, and binds oxygen with greater affinity than adult hemoglobin. This means that the oxygen binding curve for fetal hemoglobin is left-shifted (i.e., a higher percentage of hemoglobin has oxygen bound to it at lower oxygen tension), in comparison to that of adult hemoglobin. As a result, fetal blood in the placenta is able to take oxygen from maternal blood.

Hemoglobin also carries nitric oxide in the globin part of the molecule. This improves oxygen delivery in the periphery and contributes to the control of respiration. NO binds reversibly to a specific cysteine residue in globin; the binding depends on the state (R or T) of the hemoglobin. The resulting S-nitrosylated hemoglobin influences various NO-related activities such as the control of vascular resistance, blood pressure and respiration. NO is not released in the cytoplasm of erythrocytes but transported by an anion exchanger called AE1 out of them.[49]

A study was performed to examine the influence of the form of hemoglobin (Hb) on the partitioning of inhaled volatile organic compounds (VOCs) into [human and animal] blood. Benzene was the prototypic VOC used in the investigations for this research due to the similar properties it shares with many other VOCs. To be specific, this study analyses the influence of the water solubility of Hb on the partitioning coefficient (PC) of a VOC as compared to the influence of the "species" or form of Hb. The different forms of blood used include: human hemoglobin (HbA), rat Hb, and sickle-cell hemoglobin (HbS). Rat Hb contains little water and is in a quasi-crystalline form, found inside the red blood cells (RBC), meaning they are more hydrophobic than human Hb, which are water-soluble. Sickle-cell hemoglobin (HbS) is water-soluble, however it can become water-insoluble, forming hydrophobic polymers, when deoxygenated. The findings state that the benzene PC for rat Hb was much higher than human that for Hb; however, the tests that measured the PCs of the oxygenated and deoxygenated forms of HbA and HbS did not differ, indicating that the affinity of benzene was not affected by the water solubility of Hb.[50]

Types in humans

Hemoglobin variants are a part of the normal embryonic and fetal development, but may also be pathologic mutant forms of hemoglobin in a population, caused by variations in genetics. Some well-known hemoglobin variants such as sickle-cell anemia are responsible for diseases, and are considered hemoglobinopathies. Other variants cause no detectable pathology, and are thus considered non-pathological variants.[51][52]

In the embryo:

Gower 1 (ζ2ε2)

Gower 2 (α2ε2) (PDB 1A9W)

Hemoglobin Portland (ζ2γ2).

In the fetus:

Hemoglobin F (α2γ2) (PDB 1FDH).

In adults:

Hemoglobin A (α2β2) (PDB 1BZ0) - The most common with a normal amount over 95%

Hemoglobin A2 (α2δ2) - δ chain synthesis begins late in the third trimester and in adults, it has a normal range of 1.5-3.5%

Hemoglobin F (α2γ2) - In adults Hemoglobin F is restricted to a limited population of red cells called F-cells. However, the level of Hb F can be elevated in persons with sickle-cell disease and beta-thalassemia.

Gene expression of hemoglobin before and after birth. Also identifies the types of cells and organs in which the gene expression (data on Wood W.G., (1976). Br. Med. Bull. 32, 282.)

Variant forms that cause disease:

Hemoglobin H (β4) - A variant form of hemoglobin, formed by a tetramer of β chains, which may be present in variants of α thalassemia.

Hemoglobin Barts (γ4) - A variant form of hemoglobin, formed by a tetramer of γ chains, which may be present in variants of α thalassemia.

Hemoglobin S (α2βS2) - A variant form of hemoglobin found in people with sickle cell disease. There is a variation in the β-chain gene, causing a change in the properties of hemoglobin, which results in sickling of red blood cells.

Hemoglobin C (α2βC2) - Another variant due to a variation in the β-chain gene. This variant causes a mild chronic hemolytic anemia.

Hemoglobin E (α2βE2) - Another variant due to a variation in the β-chain gene. This variant causes a mild chronic hemolytic anemia.

Hemoglobin AS - A heterozygous form causing Sickle cell trait with one adult gene and one sickle cell disease gene

Hemoglobin SC disease - A compound heterozygous form with one sickle gene and another encoding Hemoglobin C.

Degradation in vertebrate animals

When red cells reach the end of their life due to aging or defects, they are broken down in spleen, the hemoglobin molecule is broken up and the iron gets recycled. This process also produces one molecule of carbon monoxide for every molecule of heme degraded.[53] This is one of the few natural sources of carbon monoxide production in the human body, and is responsible for the normal blood levels of carbon monoxide even in people breathing pure air. The other major final product of heme degradation is bilirubin. Increased levels of this chemical are detected in the blood if red cells are being destroyed more rapidly than usual. Improperly degraded hemoglobin protein or hemoglobin that has been released from the blood cells too rapidly can clog small blood vessels, especially the delicate blood filtering vessels of the kidneys, causing kidney damage. Iron is removed from heme and salvaged for later use, it is stored as hemosiderin or ferritin in tissues and transported in plasma by beta globulins as transferins. When the porphyrin ring is broken up, the fragments are normally secreted as a yellow pigment called bilirubin, which is secreted into the intestines as bile. Intestines metabolise bilirubin into urobilinogen. Urobilinogen leaves the body in faeces, in a pigment called stercobilin. Globulin is metabolised into amino acids which are then released into circulation.

Role in disease

In sickle cell hemoglobin (HbS) glutamic acid in position 6 (in beta chain) is mutated to valine. This change allows the deoxygenated form of the hemoglobin to stick to itself.

Hemoglobin deficiency can be caused either by decreased amount of hemoglobin molecules, as in anemia, or by decreased ability of each molecule to bind oxygen at the same partial pressure of oxygen. Hemoglobinopathies (genetic defects resulting in abnormal structure of the hemoglobin molecule)[54] may cause both. In any case, hemoglobin deficiency decreases blood oxygen-carrying capacity. Hemoglobin deficiency is, in general, strictly distinguished from hypoxemia, defined as decreased partial pressure of oxygen in blood,[55][56][57][58] although both are causes of hypoxia (insufficient oxygen supply to tissues).

Other common causes of low hemoglobin include loss of blood, nutritional deficiency, bone marrow problems, chemotherapy, kidney failure, or abnormal hemoglobin (such as that of sickle-cell disease).

High hemoglobin levels may be caused by exposure to high altitudes, smoking, dehydration, or tumors.[30]

The ability of each hemoglobin molecule to carry oxygen is normally modified by altered blood pH or CO2, causing an altered oxygen–hemoglobin dissociation curve. However, it can also be pathologically altered in, e.g., carbon monoxide poisoning.

Decrease of hemoglobin, with or without an absolute decrease of red blood cells, leads to symptoms of anemia. Anemia has many different causes, although iron deficiency and its resultant iron deficiency anemia are the most common causes in the Western world. As absence of iron decreases heme synthesis, red blood cells in iron deficiency anemia are hypochromic (lacking the red hemoglobin pigment) and microcytic (smaller than normal). Other anemias are rarer. In hemolysis (accelerated breakdown of red blood cells), associated jaundice is caused by the hemoglobin metabolite bilirubin, and the circulating hemoglobin can cause renal failure.

Some mutations in the globin chain are associated with the hemoglobinopathies, such as sickle-cell disease and thalassemia. Other mutations, as discussed at the beginning of the article, are benign and are referred to merely as hemoglobin variants.

There is a group of genetic disorders, known as the porphyrias that are characterized by errors in metabolic pathways of heme synthesis. King George III of the United Kingdom was probably the most famous porphyria sufferer.

To a small extent, hemoglobin A slowly combines with glucose at the terminal valine (an alpha aminoacid) of each β chain. The resulting molecule is often referred to as Hb A1c. As the concentration of glucose in the blood increases, the percentage of Hb A that turns into Hb A1c increases. In diabetics whose glucose usually runs high, the percent Hb A1c also runs high. Because of the slow rate of Hb A combination with glucose, the Hb A1c percentage is representative of glucose level in the blood averaged over a longer time (the half-life of red blood cells, which is typically 50–55 days).

Glycosylated hemoglobin is the form of hemoglobin to which glucose is bound. The binding of glucose to amino acids in the hemoglobin takes place spontaneously (without the help of an enzyme) in many proteins, and is not known to serve a useful purpose. However, the binding to hemoglobin does serve as a record for average blood glucose levels over the lifetime of red cells, which is approximately 120 days. The levels of glycosylated hemoglobin are therefore measured in order to monitor the long-term control of the chronic disease of type 2 diabetes mellitus (T2DM). Poor control of T2DM results in high levels of glycosylated hemoglobin in the red blood cells. The normal reference range is approximately 4–5.9 %. Though difficult to obtain, values less than 7% are recommended for people with T2DM. Levels greater than 9% are associated with poor control of the glycosylated hemoglobin, and levels greater than 12% are associated with very poor control. Diabetics who keep their glycosylated hemoglobin levels close to 7% have a much better chance of avoiding the complications that may accompany diabetes (than those whose levels are 8% or higher).[59] In addition, increased glycosylation of hemoglobin increases its affinity for oxygen, therefore preventing its release at the tissue and inducing a level of hypoxia in extreme cases.[60]

Elevated levels of hemoglobin are associated with increased numbers or sizes of red blood cells, called polycythemia. This elevation may be caused by congenital heart disease, cor pulmonale, pulmonary fibrosis, too much erythropoietin, or polycythemia vera.[61]

A recent study done in Pondicherry, India, shows its importance in coronary artery disease.[62]

Diagnostic uses

Main article: Hemoglobinometer

Hemoglobin concentration measurement is among the most commonly performed blood tests, usually as part of a complete blood count. For example it is typically tested before or after blood donation. Results are reported in g/L, g/dL or mol/L. 1 g/dL equals about 0.6206  mmol/L, although the latter units are not used as often due to uncertainty regarding the polymeric state of the molecule.[63] This conversion factor, using the single globin unit molecular weight of 16,000 Da, is more common for hemoglobin concentration in blood. For MCHC the conversion factor 0.155, which uses the tetramer weight of 64,500 Da, is more common[64]. Normal levels are:

Men: 13.8 to 18.0 g/dL (138 to 180 g/L, or 8.56 to 11.17 mmol/L)

Women: 12.1 to 15.1 g/dL (121 to 151 g/L, or 7.51 to 9.37 mmol/L)

Children: 11 to 16 g/dL (111 to 160 g/L, or 6.83 to 9.93 mmol/L)

Pregnant women: 11 to 14 g/dL (110 to 140 g/L, or 6.83 to 8.69 mmol/L)[65][66]

Normal values of hemoglobin in the 1st and 3rd trimesters of pregnant women must be at least 11 g/dL and at least 10.5 g/dL during the 2nd trimester.[67]

Dehydration or hyperhydration can greatly influence measured hemoglobin levels. Albumin can indicate hydration status.

If the concentration is below normal, this is called anemia. Anemias are classified by the size of red blood cells, the cells that contain hemoglobin in vertebrates. The anemia is called "microcytic" if red cells are small, "macrocytic" if they are large, and "normocytic" otherwise.

Hematocrit, the proportion of blood volume occupied by red blood cells, is typically about three times the hemoglobin concentration measured in g/dL. For example, if the hemoglobin is measured at 17 g/dL, that compares with a hematocrit of 51%.[68]

Laboratory hemoglobin test methods require a blood sample (arterial, venous, or capillary) and analysis on hematology analyzer and CO-oximeter. Additionally, a new noninvasive hemoglobin (SpHb) test method called Pulse CO-Oximetry is also available with comparable accuracy to invasive methods.[69]

Concentrations of oxy- and deoxyhemoglobin can be measured continuously, regionally and noninvasively using NIRS.[70][71][72][73][74] NIRS can be used both on the head as on muscles. This technique is often used for research in e.g. elite sports training, ergonomics, rehabilition, patient monitoring, neonatal research, functional brain monitoring, brain computer interface, urology (bladder contraction), neurology (Neurovascular coupling) and more.

Long-term control of blood sugar concentration can be measured by the concentration of Hb A1c. Measuring it directly would require many samples because blood sugar levels vary widely through the day. Hb A1c is the product of the irreversible reaction of hemoglobin A with glucose. A higher glucose concentration results in more Hb A1c. Because the reaction is slow, the Hb A1c proportion represents glucose level in blood averaged over the half-life of red blood cells, is typically 50–55 days. An Hb A1c proportion of 6.0% or less show good long-term glucose control, while values above 7.0% are elevated. This test is especially useful for diabetics.[75]

The functional magnetic resonance imaging (fMRI) machine uses the signal from deoxyhemoglobin, which is sensitive to magnetic fields since it is paramagnetic. Combined measurement with NIRS shows good correlation with both the oxy- and deoxyhemoglobin signal compared to the BOLD signal.[76]

Analogues in non-vertebrate organisms

A variety of oxygen-transport and -binding proteins exist in organisms throughout the animal and plant kingdoms. Organisms including bacteria, protozoans, and fungi all have hemoglobin-like proteins whose known and predicted roles include the reversible binding of gaseous ligands. Since many of these proteins contain globins and the heme moiety (iron in a flat porphyrin support), they are often called hemoglobins, even if their overall tertiary structure is very different from that of vertebrate hemoglobin. In particular, the distinction of "myoglobin" and hemoglobin in lower animals is often impossible, because some of these organisms do not contain muscles. Or, they may have a recognizable separate circulatory system but not one that deals with oxygen transport (for example, many insects and other arthropods). In all these groups, heme/globin-containing molecules (even monomeric globin ones) that deal with gas-binding are referred to as oxyhemoglobins. In addition to dealing with transport and sensing of oxygen, they may also deal with NO, CO2, sulfide compounds, and even O2 scavenging in environments that must be anaerobic. They may even deal with detoxification of chlorinated materials in a way analogous to heme-containing P450 enzymes and peroxidases.

The giant tube worm Riftia pachyptila showing red hemoglobin-containing plumes

The structure of hemoglobins varies across species. Hemoglobin occurs in all kingdoms of organisms, but not in all organisms. Primitive species such as bacteria, protozoa, algae, and plants often have single-globin hemoglobins. Many nematode worms, molluscs, and crustaceans contain very large multisubunit molecules, much larger than those in vertebrates. In particular, chimeric hemoglobins found in fungi and giant annelids may contain both globin and other types of proteins.[77]

One of the most striking occurrences and uses of hemoglobin in organisms is in the giant tube worm (Riftia pachyptila, also called Vestimentifera), which can reach 2.4 meters length and populates ocean volcanic vents. Instead of a digestive tract, these worms contain a population of bacteria constituting half the organism's weight. The bacteria react with H2S from the vent and O2 from the water to produce energy to make food from H2O and CO2. The worms end with a deep red fan-like structure ("plume"), which extends into the water and absorbs H2S and O2 for the bacteria, and CO2 for use as synthetic raw material similar to photosynthetic plants. The structures are bright-red due to their containing several extraordinarily complex hemoglobins that have up to 144 globin chains, each including associated heme structures. These hemoglobins are remarkable for being able to carry oxygen in the presence of sulfide, and even to carry sulfide, without being completely "poisoned" or inhibited by it as hemoglobins in most other species are.[78][79]

Other oxygen-binding proteins

Myoglobin

Found in the muscle tissue of many vertebrates, including humans, it gives muscle tissue a distinct red or dark gray color. It is very similar to hemoglobin in structure and sequence, but is not a tetramer; instead, it is a monomer that lacks cooperative binding. It is used to store oxygen rather than transport it.

Hemocyanin

The second most common oxygen-transporting protein found in nature, it is found in the blood of many arthropods and molluscs. Uses copper prosthetic groups instead of iron heme groups and is blue in color when oxygenated.

Hemerythrin

Some marine invertebrates and a few species of annelid use this iron-containing non-heme protein to carry oxygen in their blood. Appears pink/violet when oxygenated, clear when not.

Chlorocruorin

Found in many annelids, it is very similar to erythrocruorin, but the heme group is significantly different in structure. Appears green when deoxygenated and red when oxygenated.

Vanabins

Also known as vanadium chromagens, they are found in the blood of sea squirts. There were once hypothesized to use the rare metal vanadium as an oxygen binding prosthetic group. However, although they do contain vanadium by preference, they apparently bind little oxygen, and thus have some other function, which has not been elucidated (sea squirts also contain some hemoglobin). They may act as toxins.

Erythrocruorin

Found in many annelids, including earthworms, it is a giant free-floating blood protein containing many dozens—possibly hundreds—of iron- and heme-bearing protein subunits bound together into a single protein complex with a molecular mass greater than 3.5 million daltons.

Pinnaglobin

Only seen in the mollusc Pinna squamosa. Brown manganese-based porphyrin protein.

Leghemoglobin

In leguminous plants, such as alfalfa or soybeans, the nitrogen fixing bacteria in the roots are protected from oxygen by this iron heme containing oxygen-binding protein. The specific enzyme protected is nitrogenase, which is unable to reduce nitrogen gas in the presence of free oxygen.

Coboglobin

A synthetic cobalt-based porphyrin. Coboprotein would appear colorless when oxygenated, but yellow when in veins.

Presence in nonerythroid cells

Some nonerythroid cells (i.e., cells other than the red blood cell line) contain hemoglobin. In the brain, these include the A9 dopaminergic neurons in the substantia nigra, astrocytes in the cerebral cortex and hippocampus, and in all mature oligodendrocytes.[7] It has been suggested that brain hemoglobin in these cell may enable the "storage of oxygen to provide a homeostatic mechanism in anoxic conditions, which is especially important for A9 DA neurons that have an elevated metabolism with a high requirement for energy production".[7] It has been noted further that "A9 dopaminergic neurons may be at particular risk since in addition to their high mitochondrial activity they are under intense oxidative stress caused by the production of hydrogen peroxide via autoxidation and/or monoamine oxidase (MAO)-mediated deamination of dopamine and the subsequent reaction of accessible ferrous iron to generate highly toxic hydroxyl radicals".[7] This may explain the risk of these cells for degeneration in Parkinson's disease.[7] The hemoglobin-derived iron in these cells is not the cause of the post-mortem darkness of these cells (origin of the Latin name, substantia nigra), but rather is due to neuromelanin.

Outside the brain, hemoglobin has non-oxygen-carrying functions as an antioxidant and a regulator of iron metabolism in macrophages,[80] alveolar cells,[81] and mesangial cells in the kidney.[82]

In history, art and music

The planet Mars

Historically, the color of blood was associated with rust, as ancient Romans associated the planet Mars with the god of war since Mars is orange-red. The color of Mars is due to the iron oxide in the Martian soil, but the red in blood is not due to the iron in hemoglobin and its oxides, which is a common misconception. The red is due to the porphyrin moiety of hemoglobin to which the iron is bound, not the iron itself,[83] although the ligation and redox state of the iron can influence the pi to pi* or n to pi* electronic transitions of the porphyrin and hence its optical characteristics.

Heart of Steel (Hemoglobin) (2005) by Julian Voss-Andreae. The images show the 5' (1.60 m) tall sculpture right after installation, after 10 days, and after several months of exposure to the elements.

Artist Julian Voss-Andreae created a sculpture called "Heart of Steel (Hemoglobin)" in 2005, based on the protein's backbone. The sculpture was made from glass and weathering steel. The intentional rusting of the initially shiny work of art mirrors hemoglobin's fundamental chemical reaction of oxygen binding to iron.[84][85]

Rock band Placebo recorded a song called "Haemoglobin" with the lyrics "Haemoglobin is the key to a healthy heartbeat". French rap artist MC Solaar also had a successful single titled "La Concubine de L'Hemoglobin" in 1994.

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^ Sidell, Bruce; Kristin O'Brien (2006). "When bad things happen to good fish: the loss of hemoglobin and myoglobin expression in Antarctic icefishes". The Journal of Experimental Biology 209 (Pt 10): 1791–1802. doi:10.1242/jeb.02091. PMID 16651546.

^ Robert I. Weed, Claude F. Reed, and George Berg (1963). "IS HEMOGLOBIN AN ESSENTIAL STRUCTURAL COMPONENT OF HUMAN ERYTHROCYTE MEMBRANES?". J Clin Invest. 42 (4): 581–8. doi:10.1172/JCI104747.

^ Dominguez de Villota ED, Ruiz Carmona MT, Rubio JJ, de Andrés S (December 1981). "Equality of the in vivo and in vitro oxygen-binding capacity of haemoglobin in patients with severe respiratory disease". Br J Anaesth 53 (12): 1325–8. doi:10.1093/bja/53.12.1325. ISSN 0007-0912. PMID 7317251.

^ Costanzo, Linda S. (2007). Physiology. Hagerstwon, MD: Lippincott Williams &Wilkins. ISBN 0-7817-7311-3.

^ Respiratory Function of Hemoglobin. Connie C.W. Hsia, M.D. N Engl J Med 1998; 338:239-248 January 22, 1998

^ a b c d e Biagioli M, Pinto M, Cesselli D, et al. (September 2009). "Unexpected expression of alpha- and beta-globin in mesencephalic dopaminergic neurons and glial cells". Proc. Natl. Acad. Sci. U.S.A. 106 (36): 15454–9. doi:10.1073/pnas.0813216106. PMC 2732704. PMID 19717439. //www.ncbi.nlm.nih.gov/pmc/articles/PMC2732704/.

^ Engelhard, Johann Friedrich (1825) (in Latin). Commentatio de vera materia sanguini purpureum colorem impertientis natura. Göttingen: Dietrich.

^ Adair, Gilbert Smithson (1925). "A critical study of the direct method of measuring the osmotic pressure of hǣmoglobin". Proc. R. Soc. Lond. A 108: 292–300.

^ Hünefeld F.L. (1840). Die Chemismus in der thierischen Organization. Leipzig.

^ Funke O (1851). "Über das milzvenenblut". Z Rat Med 1: 172–218.

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^ Perutz MF (November 1960). "Structure of haemoglobin". Brookhaven symposia in biology 13: 165–83. ISSN 0068-2799. PMID 13734651.

^ A Syllabus of Human Hemoglobin Variants (1996)

^ Hemoglobin Variants

^ Uthman, MD, Ed. "Hemoglobinopathies and Thalassemias". http://web2.airmail.net/uthman/hemoglobinopathy/hemoglobinopathy.html. Retrieved 2007-12-26.

^ Reed, Leslie. "Adaptation found in mouse genes." Omaha World-Herald 11 Aug. 2009: EBSCO. Web. 30 Oct. 2009.

^ "Mammoths had ′anti-freeze′ blood". BBC. 2010-05-02. http://news.bbc.co.uk/2/hi/science/nature/8657464.stm. Retrieved 2010-05-02.

^ "Hemoglobin Synthesis". April 14, 2002. http://sickle.bwh.harvard.edu/hbsynthesis.html. Retrieved 2007-12-26.

^ a b van Kessel et al. "2.4 Proteins - Natural Polyamides." Chemistry 12. Toronto: Nelson, 2003. 122. Print.

^ "Hemoglobin Tutorial." University of Massachusetts Amherst. N.p., n.d. Web. 23 Oct. 2009. <http://www.umass.edu/molvis/tutorials/hemoglobin/index.htm>.

^ Steinberg 2001, p. 95

^ Hardison 1996, p. 1

^ "Hemoglobin." School of Chemistry - Bristol University - UK. N.p., n.d. Web. 12 Oct. 2009. <http://www.chm.bris.ac.uk/motm/hemoglobin/hemoglobjm.htm>.

^ WikiPremed >Coordination Chemistry Retrieved on July 2, 2009

^ Linberg R, Conover CD, Shum KL, Shorr RG (Mar 1998). "Hemoglobin based oxygen carriers: how much methemoglobin is too much?". Artif Cells Blood Substit Immobil Biotechnol 26 (2): 133–48. doi:10.3109/10731199809119772. ISSN 1073-1199. PMID 9564432.

^ Van Beekvelt MC, Colier WN, Wevers RA, Van Engelen BG (Feb 2001). "Performance of near-infrared spectroscopy in measuring local O2 consumption and blood flow in skeletal muscle". J Appl Physiol 90 (2): 511–519. ISSN 8750-7587. PMID 11160049. http://jap.physiology.org/cgi/pmidlookup?view=long&pmid=11160049.

^ a b "Hemoglobin." MedicineNet. N.p., n.d. Web. 12 Oct. 2009. <www.medicinenet.com/hemoglobin/article.htm>.

^ "Hemoglobin Home." Biology @ Davidson. N.p., n.d. Web. 12 Oct. 2009. <http://www.bio.davidson.edu/Courses/Molbio/MolStudents/spring2005/Heiner/hemoglobin.html>.

^ Baillie/Simpson. "Online model of the hemoglobin binding and the effects of hyperventilation". http://www.altitude.org/hemoglobin_saturation.php. Retrieved 2006-08-10.

^ Michael W King, PhD. "The Medical Biochemistry Page - Hemoglobin". http://themedicalbiochemistrypage.org/hemoglobin-myoglobin.php#hemoglobin. Retrieved 2012-03-20.

^ Voet, Voet, Pratt: Fundamentals of Biochemistry 3e / fig_07_06

^ Pin S, Alpert B, Michalowicz A. (Oct 1982). "Oxygen bonding in human hemoglobin and its isolated subunits: A XANES study". FEBS Lett. 147 (1): 106–10. doi:10.1016/0014-5793(82)81021-1. PMID 7140986.

^ S Pin, P Valat, R Cortes, A Michalowicz, and B Alpert (December 1985). "Ligand binding processes in hemoglobin. Chemical reactivity of iron studied by XANES spectroscopy". Biophys J. 48(6): 997–10.

^ A. Bianconi, A. Congiu-Castellanoa, M. Dell'Aricciaa, A. Giovannellia, E. Burattinib and P. J. Durhamc (August 1985). "Increase of the Fe effective charge in hemoproteins during oxygenation process". Biochemical and Biophysical Research Communications 30 (1): 98–102. doi:10.1016/0006-291X(85)91775-9. PMID 4038310.

^ Childs PE (2001). "Haemoglobin - a molecular lung: 2". Chemistry in Action (65). ISSN 0332-2637. http://www.ul.ie/~childsp/CinA/Issue65/TOC28_Haemoglobin.htm.

^ Chen H, Ikeda-Saito M, Shaik S (11 2008). "Nature of the Fe-O2 bonding in oxy-myoglobin: effect of the protein". Journal of the American Chemical Society 130 (44): 14778–14790. doi:10.1021/ja805434m. PMID 18847206. http://pubs.acs.org/doi/abs/10.1021/ja805434m.

^ Jensen, Frank B (4/9/2009). "The dual roles of red blood cells in tissue oxygen delivery: oxygen carriers and regulators of local blood flow". Journal of Experimental Biology (The Company of Biologists) 212 (Pt 21): 3387–3393. doi:10.1242/jeb.023697. PMID 19837879.

^ Chou KC (June 1989). "Low-frequency resonance and cooperativity of hemoglobin". Trends Biochem. Sci. 14 (6): 212–3. doi:10.1016/0968-0004(89)90026-1. PMID 2763333.

^ Guyton A C: Medical Physiology 12ed. 2010, page 502

^ Nelson, D. L.; Cox, M. M. (2000). Lehninger Principles of Biochemistry, 3rd ed. New York, NY: Worth Publishers. p 217

^ Guyton, Arthur C.; John E. Hall (2006). Textbook of Medical Physiology (11 ed.). Philadelphia: Elsevier Saunders. p. 511. ISBN 0-7216-0240-1.

^ "YouTube - Lecture - 12 Myoglobin and Hemoglobin." YouTube - Broadcast Yourself.. N.p., n.d. Web. 30 Oct. 2009. <http://www.youtube.com/watch?v=6AfRX6oh9-E>.

^ Rutjes, H. A.; Nieveen, M. C.; Weber, R. E.; Witte, F.; Van den Thillart, G. E. E. J. M. (20 June 2007). "Multiple strategies of Lake Victoria cichlids to cope with lifelong hypoxia include hemoglobin switching". AJP: Regulatory, Integrative and Comparative Physiology 293 (3): R1376–R1383. doi:10.1152/ajpregu.00536.2006.

^ Gronenborn, Angela M.; Clore, G.Marius; Brunori, Maurizio; Giardina, Bruno; Falcioni, Giancarlo; Perutz, Max F.. "Stereochemistry of ATP and GTP bound to fish haemoglobins". Journal of Molecular Biology 178 (3): 731–742. doi:10.1016/0022-2836(84)90249-3.

^ Weber, Roy E.; Frank B. Jensen (1988). "Functional adaptations in hemoglobins from ectothermic invertebrates". Annual Review of Physiology 50: 161-179.

^ Rang, H.P.; Dale M.M., Ritter J.M., Moore P.K. (2003). Pharmacology, Fifth Edition. Elsevier. ISBN 0-443-07202-7.

^ Wiester et al. "Partitioning of Benzene in Blood: Influence of Hemoglobin Type in Humans and Animals." Environmental Health Perspectives 110.3 (2002): p255-261. EBSCO. Web. 1 Nov. 2009.

^ "Hemoglobin Variants". Lab Tests Online. American Association for Clinical Chemistry. 2007-11-10. http://www.labtestsonline.org/understanding/analytes/hemoglobin_var/glance-3.html. Retrieved 2008-10-12.

^ Huisman THJ (1996). "A Syllabus of Human Hemoglobin Variants". Globin Gene Server. Pennsylvania State University. http://globin.cse.psu.edu/html/huisman/variants/. Retrieved 2008-10-12.

^ Kikuchi, G.; Yoshida, T.; Noguchi, M. (2005). "Heme oxygenase and heme degradation". Biochemical and Biophysical Research Communications 338 (1): 558–567. doi:10.1016/j.bbrc.2005.08.020. PMID 16115609. edit

^ "hemoglobinopathy" at Dorland's Medical Dictionary

^ britannica.com --> blood disease, stating hypoxemia (reduced oxygen tension in the blood). Retrieved on May 25, 2009

^ Biology-Online.org --> Dictionary » H » Hypoxemia last modified 00:05, 29 December 2008

^ Page 430 -> Pathophysiology of acute respiratory failure in Trauma By William C. Wilson, Christopher M. Grande, David B. Hoyt Edition: illustrated Published by CRC Press, 2007 ISBN 0-8247-2920-X, 9780824729202 1384 pages

^ Hazards of hypoxemia: How to protect your patient from low oxygen levels In Nursing , May 1996 by McGaffigan, Patricia A

^ "Definition of Glycosylated Hemoglobin." Medicine Net. N.p., n.d. Web. 12 Oct. 2009. <www.medterms.com/script/main/art.asp?articlekey=16295>.

^ Madsen, H; Ditzel, J (1984). "Blood-oxygen transport in first trimester of diabetic pregnancy.". Acta Obstetricia et Gynecologica Scandinavica 63 (4): 317–20. PMID 6741458. http://www.ncbi.nlm.nih.gov/pubmed/6741458.

^ Hemoglobin at Medline Plus

^ Padmanaban P, Toora BD. Hemoglobin: Emerging marker in stable coronary artery disease. Chron Young Sci [serial online] 2011 [cited 2011 Jul 24];2:109-10. Available from: http://www.cysonline.org/text.asp?2011/2/2/109/82971.

^ Society for Biomedical Diabetes Research http://www.soc-bdr.org/rds/authors/unit_tables_conversions_and_genetic_dictionaries/e5196/index_en.html

^ Robert I. Handin; Samuel E. Lux; and Thomas P. StosselBlood (2003). Principles &Practice of Hematology. Lippincott Williams &Wilkins

^ Hemoglobin Level Test

^ Although other sources can have slightly differing values, such as http://www.gpnotebook.co.uk/simplepage.cfm?ID=1026883654

^ Murray S.S. &McKinney E.S.(2006). Foundations of Maternal-Newborn Nursing.(4th ed., p 919).Philadelphia: Saunders Elsevier

^ "Hematocrit (HCT) or Packed Cell Volume (PCV)". DoctorsLounge.com. http://www.doctorslounge.com/hematology/labs/hematocrit.htm. Retrieved 2007-12-26.

^ Frasca D., Dahyot-Fizelier C., Catherine K., Levrat Q., Debaene B., Mimoz O. Crit Care Med. 2011 Oct;39(10):2277-82.

^ Ferrari, M, Binzoni, T and Quaresima, V; Oxidative metabolism in muscle. Phil Trans R Soc Lond B 1997; 352: 677-683.

^ Madsen, PL, Secher NH. Near infrared oximetry of the brain. Prog Neurobiol 1999; 58: 541-560

^ McCully KK, Hamaoka T. Near-infrared spectroscopy: what can it tell us about oxygen saturation in skeletal muscle? Exerc Sport Sci Rev 2000: 123-127.

^ Perrey S. Non-invasive NIR spectroscopy of human brain function during exercise. Methods. 2008 Aug;45(4):289-99.

^ Rolfe, P. In vivo near-infrared spectroscopy. Ann Rev Biomed Eng 2000; 2: 715-754.

^ This Hb A1c level is only useful in individuals who have red blood cells (RBCs) with normal survivals (i.e., normal half-life). In individuals with abnormal RBCs, whether due to abnormal hemoglobin molecules (such as Hemoglobin S in Sickle Cell Anemia) or RBC membrane defects - or other problems, the RBC half-life is frequently shortened. In these individuals, an alternative test called "fructosamine level" can be used. It measures the degree of glycation (glucose binding) to albumin, the most common blood protein, and reflects average blood glucose levels over the previous 18-21 days, which is the half-life of albumin molecules in the circulation.

^ Mehagnoul-Schipper, DJ; van der Kallen, BF; Colier, WNJM; van der Sluijs, MC; van Erning, LJ; Thijssen, HO; Oeseburg, B; Hoefnagels, WH et al. (2002). "Simultaneous measurements of cerebral oxygenation changes during brain activation by near-infrared spectroscopy and functional magnetic resonance imaging in healthy young and elderly subjects.". Hum Brain Mapp 16 (1): 14–23. doi:10.1002/hbm.10026.

^ Weber RE, Vinogradov SN (Apr 2001). "Nonvertebrate hemoglobins: functions and molecular adaptations". Physiol. Rev. 81 (2): 569–628. ISSN 0031-9333. PMID 11274340. http://physrev.physiology.org/cgi/pmidlookup?view=long&pmid=11274340.

^ Zal F, Lallier FH, Green BN, Vinogradov SN, Toulmond A (Apr 1996). "The multi-hemoglobin system of the hydrothermal vent tube worm Riftia pachyptila. II. Complete polypeptide chain composition investigated by maximum entropy analysis of mass spectra". J. Biol. Chem. 271 (15): 8875–81. doi:10.1074/jbc.271.15.8875. ISSN 0021-9258. PMID 8621529. http://www.jbc.org/cgi/pmidlookup?view=long&pmid=8621529.

^ Minic Z, Hervé G (Aug 2004). "Biochemical and enzymological aspects of the symbiosis between the deep-sea tubeworm Riftia pachyptila and its bacterial endosymbiont". Eur. J. Biochem. 271 (15): 3093–102. doi:10.1111/j.1432-1033.2004.04248.x. ISSN 0014-2956. PMID 15265029.

^ Liu L, Zeng M, Stamler JS (June 1999). "Hemoglobin induction in mouse macrophages". Proceedings of the National Academy of Sciences of the United States of America 96 (12): 6643–7. doi:10.1073/pnas.96.12.6643. PMC 21968. PMID 10359765. //www.ncbi.nlm.nih.gov/pmc/articles/PMC21968/.

^ Newton DA, Rao KM, Dluhy RA, Baatz JE (March 2006). "Hemoglobin Is Expressed by Alveolar Epithelial Cells". Journal of Biological Chemistry 281 (9): 5668–76. doi:10.1074/jbc.M509314200. PMID 16407281. http://www.jbc.org/cgi/reprint/281/9/5668.

^ Nishi H, Inagi R, Kato H, et al. (August 2008). "Hemoglobin Is Expressed by Mesangial Cells and Reduces Oxidant Stress". Journal of the American Society of Nephrology 19 (8): 1500–8. doi:10.1681/ASN.2007101085. PMC 2488266. PMID 18448584. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=18448584.

^ Boh, Larry (2001). Pharmacy Practice Manual: A Guide to the Clinical Experience. Lippincott Williams &Wilkins. ISBN 0-7817-2541-0.

^ Holden, Constance (30 September 2005). "Blood and Steel" (pdf). Science 309 (5744): 2160. doi:10.1126/science.309.5744.2160d. http://www.sciencemag.org/cgi/reprint/309/5744/2160d.pdf.

^ Moran L, Horton RA, Scrimgeour G, Perry M (2011). Principles of Biochemistry. Boston, MA: Pearson. pp. 127. ISBN 0-321-70733-8.

출처: http://en.wikipedia.org/wiki/Hemoglobin

* 대부분 친족결혼으로 생기는 것은 아니나, 친족결혼인 경우 발생률이 높다	(table7.2).

* 아프리카 흑인 3명 중 1명이 보인자, 40 명 중 1명이 낫세포 빈혈증이다. 이와	같이 고빈도 발생의 원인은 보인자의 경우 말라리아에 내성이 있기  때문.

- 지금 까지 1730 가지의 상염색체성 열성유전이 알려짐

- 15% 정도에서 효소 결핍증이 알려졌으며, 나머지도 효소결핍에 의한 것이 대부분일 것으로 보임.

- 어떤 경우는 돌연변이가 서로 다른 여러 부위에 일어날 수 있다(multiple allellism). 두개의 서로다른 돌연변이 대립인자를 갖는 개체의 경우 genetic compound(An individual who has two different abnormal alleles at a particular locus, one on each chromosome of a pair; usually refers to individuals affected with an autosomal recessive disorder 또는 In genetics, a compound heterozygote is an organism that has two different alleles, both mutated, at the same locus. That is, for a locus A with normal allele A and mutant alleles a1 and a2, a compound heterozygote will be a1/a2.) 라고 함.

예) Mutations of the gap junction beta 2 (GJB2) gene coding for the protein connexin 26 account for up to 50% of nonsyndromic sensorineural hearing loss (NSHL), with specific mutations associated with distinct ethnic groups.  The two affected children were found to be compound heterozygotes for Cx26 mutations, displaying a previously unreported combination of 35delG and 235delC. The parents were each unaffected heterozygotes consistent with their ethnic heritage, specifically, the Caucasian mother a 35delG heterozygote and the Chinese father a 235delC heterozygote.

- 단일 유전자 이상으로 알고 있던 많은 경우의 유전질환에 있어서, 실제로 유전적으로 이질적인 경우가 있다. 즉 겉으로 동일한 유전질환일 경우라 할지라도 그 유전적 원인이 여러 가지 서로 다름. 서로 다른 가족에서 그 유전 형태가 다르게 나타나거나, 상염색체성 열성인 부모의 자식이 정상으로만 나타날 때 genetic heterogeneity (The presence of apparently similar characters for which the genetic evidence indicates that different genes or different genetic mechanisms are involved in different pedigrees or presence of a variety of genetic defects which cause the same disease)로 볼 수 있다.

7.4 상염색체성 공동우성 유전

- 상염색체성 우성유전의 형식과 동일하나. 두 형질이 구별되며 모두 발현됨(Table 7.5)

7.5 상염색체성 유전의 특징:Table 7.6

Rh blood group system

The Rh (Rhesus) blood group system (including the Rh factor) is one of thirty current human blood group systems. Clinically, it is the most important blood group system after ABO. At present, the Rh blood group system consists of 50 defined blood-group antigens, among which the five antigens D, C, c, E, and e are the most important. The commonly used terms Rh factor, Rh positive and Rh negative refer to the D antigen only. Besides its role in blood transfusion, the Rh blood group system—specifically, the D antigen—is used to determine the risk of hemolytic disease of the newborn (or erythroblastosis fetalis) as prevention is key.

Contents

1 Rh factor

2 History of discoveries

3 Rh nomenclature

4 Rh system antigens

5 Hemolytic disease of the newborn

6 Population data

7 Inheritance

8 Function

9 Origin of RHD polymorphism

10 Weak D

11 Other Rh group antigens

12 References

13 External links

Rh factor

An individual either has, or does not have, the "Rhesus factor" on the surface of their red blood cells. This term strictly refers only to the most immunogenic D antigen of the Rh blood group system, or the Rh- blood group system. The status is usually indicated by Rh positive (Rh+ does have the D antigen) or Rh negative (Rh- does not have the D antigen) suffix to the ABO blood type. However, other antigens of this blood group system are also clinically relevant. These antigens are listed separately (see below: Rh nomenclature). In contrast to the ABO blood group, immunization against Rh can generally only occur through blood transfusion or placental exposure during pregnancy in women.

History of discoveries

In 1939, Drs. Philip Levine and Rufus Stetson published in a first case report the clinical consequences of non-recognized Rh factor, hemolytic transfusion reaction and hemolytic disease of the newborn in its most severe form.[1] It was recognized that the serum of the reported woman agglutinated with red blood cells of about 80% of the people although the then known blood groups, in particular ABO were matched. No name was given to this then for the first time described agglutinin. In 1940, Drs. Karl Landsteiner and Alexander S. Wiener reported a serum that also reacted with about 85% of different human red blood cells.[2] This serum was produced by immunizing rabbits with red blood cells from Rhesus macaque. The antigen that induced this immunization was designated by them as Rh factor "to indicate that rhesus blood had been used for the production of the serum."[3]

Based on the serologic similarities Rh factor was later also used for antigens, and anti-Rh for antibodies, found in humans such as the previously described by Levine and Stetson. Although differences between these two sera were shown already in 1942 and clearly demonstrated in 1963, the already widely used term "Rh" was kept for the clinically described human antibodies which are different from the ones related to the Rhesus monkey. This real factor found in Rhesus macaque was classified in the Landsteiner-Wiener antigen system (antigen LW, antibody anti-LW) in honor of the discoverers.[4][5] It was recognized that the Rh factor was just one in a system of various antigens. Based on different models of genetic inheritance, two different terminologies were developed; both of them are still in use

The clinical significance of this highly immunizing D antigen (i.e. Rh factor) was soon realized. Some keystones were to recognize its importance for blood transfusion including reliable diagnostic tests, and hemolytic disease of the newborn including exchange transfusion and very importantly the prevention of it by screening and prophylaxis.

The discovery of fetal free DNA in maternal circulation by Holzgrieve et al. led to the noninvasive genotyping of fetal Rh genes in many countries.

Rh nomenclature

The Rh blood group system has two sets of nomenclatures: one developed by Ronald Fisher and R.R. Race, the other by Wiener. Both systems reflected alternative theories of inheritance. The Fisher-Race system, which is more commonly in use today, uses the CDE nomenclature. This system was based on the theory that a separate gene controls the product of each corresponding antigen (e.g., a "D gene" produces D antigen, and so on). However, the d gene was hypothetical, not actual.

The Wiener system used the Rh-Hr nomenclature. This system was based on the theory that there was one gene at a single locus on each chromosome, each contributing to production of multiple antigens. In this theory, a gene R1 is supposed to give rise to the “blood factors” Rh0, rh’, and hr” (corresponding to modern nomenclature of the D, C and e antigens) and the gene r to produce hr’ and hr” (corresponding to modern nomenclature of the c and e antigens).[6]

Notations of the two theories are used interchangeably in blood banking (e.g., Rho(D) meaning RhD positive). Wiener's notation is more complex and cumbersome for routine use. Because it is simpler to explain, the Fisher-Race theory has become more widely used.

DNA testing has shown that both theories are partially correct.[citation needed] There are in fact two linked genes, the RHD gene which produces a single immune specificity (anti-D) and the RHCE gene with multiple specificities (anti-C, anti-c, anti-E, anti-e). Thus, Wiener's postulate that a gene could have multiple specificities (something many did not give credence to originally) has been proven correct. On the other hand, Wiener's theory that there is only one gene has proven incorrect, as has the Fischer-Race theory that there are three genes, rather than the 2. The CDE notation used in the Fisher-Race nomenclature is sometimes rearranged to DCE to more accurately represent the co-location of the C and E encoding on the RhCE gene, and to make interpretation easier.

Rh system antigens

The proteins which carry the Rh antigens are transmembrane proteins, whose structure suggest that they are ion channels.[7] The main antigens are D, C, E, c and e, which are encoded by two adjacent gene loci, the RHD gene which encodes the RhD protein with the D antigen (and variants)[8] and the RHCE gene which encodes the RhCE protein with the C, E, c and e antigens (and variants).[9] There is no d antigen. Lowercase "d" indicates the absence of the D antigen (the gene is usually deleted or otherwise nonfunctional).

Rh phenotypes are readily identified by identifying the presence or absence of the Rh surface antigens. As can be seen in the table below, most of the Rh phenotypes can be produced by several different Rh genotypes. The exact genotype of any individual can only be identified by DNA analysis. Regarding patient treatment, only the phenotype is usually of any clinical significance to ensure a patient is not exposed to an antigen they are likely to develop antibodies against. A probable genotype may be speculated on, based on the statistical distributions of genotypes in the patient's place of origin.

Phenotype expressed on cell	Genotype expressed in DNA		Prevalence (%) †
	Fisher-Race notation	Wiener notation
D+ C+ E+ c+ e+ (RhD+)	Dce/DCE	R0RZ	0.0125
	Dce/dCE	R0rY	0.0003
	DCe/DcE	R1R2	11.8648
	DCe/dcE	R1r’’	0.9992
	DcE/dCe	R2r’	0.2775
	DCE/dce	RZr	0.1893
D+ C+ E+ c+ e- (RhD+)	DcE/DCE	R2RZ	0.0687
	DcE/dCE	R2rY	0.0014
	DCE/dcE	RZr’’	0.0058
D+ C+ E+ c- e+ (RhD+)	DCe/dCE	R1rY	0.0042
	DCE/dCe	RZr’	0.0048
	DCe/DCE	R1RZ	0.2048
D+ C+ E+ c- e- (RhD+)	DCE/DCE	RZRZ	0.0006
	DCE/dCE	RZrY	<0.0001
D+ C+ E- c+ e+ (RhD+)	Dce/dCe	R0r’	0.0505
	DCe/dce	R1r	32.6808
	DCe/Dce	R1R0	2.1586
D+ C+ E- c- e+ (RhD+)	DCe/DCe	R1R1	17.6803
	DCe/dCe	R1r’	0.8270
D+ C- E+ c+ e+ (RhD+)	DcE/Dce	R2R0	0.7243
	Dce/dcE	R0r’’	0.0610
	DcE/dce	R2r	10.9657
D+ C- E+ c+ e- (RhD+)	DcE/DcE	R2R2	1.9906
	DcE/dcE	R2r’’	0.3353
D+ C- E- c+ e+ (RhD+)	Dce/Dce	R0R0	0.0659
	Dce/dce	R0r	1.9950
D- C+ E+ c+ e+ (RhD-)	dce/dCE	rrY	0.0039
	dCe/dcE	r’r’’	0.0234
D- C+ E+ c+ e- (RhD-)	dcE/dCE	r’’rY	0.0001
D- C+ E+ c- e+ (RhD-)	dCe/dCE	r’rY	0.0001
D- C+ E+ c- e- (RhD-)	dCE/dCE	rYrY	<0.0001
D- C+ E- c+ e+ (RhD-)	dce/dCe	rr’	0.7644
D- C+ E- c- e+ (RhD-)	dCe/dCe	r’r’	0.0097
D- C- E+ c+ e+ (RhD-)	dce/dcE	rr’’	0.9235
D- C- E+ c+ e- (RhD-)	dcE/dcE	r’’r’’	0.0141
D- C- E- c+ e+ (RhD-)	dce/dce	rr	15.1020

† Figures taken from a study performed in 1948 on a sample of 2000 people in the United Kingdom.[10] Note that the R0 haplotype is much more common in people of sub-Saharan African origin.

Rh Phenotype	CDE	Patients (%)	Donors (%)
R 1r	CcDe	37.4	33.0
R 1R 2	CcDEe	35.7	30.5
R 1R 1	CDe	5.7	21.8
rr	ce	10.3	11.6
R 2r	cDEe	6.6	10.4
R 0R 0	cDe	2.8	2.7
R 2R 2	cDE	2.8	2.4
rr’’	cEe	–	0.98
R ZR Z	CDE	–	0.03
rr’	Cce	0.8	–

Hemolytic disease of the newborn

Main article: Hemolytic disease of the newborn

The hemolytic condition occurs when there is an incompatibility between the blood types of the mother and the fetus. There is also potential incompatibility if the mother is Rh negative and the father is positive. When any incompatibility is detected, the mother receives an injection at 28 weeks gestation and at birth to avoid the development of antibodies toward the fetus. These terms do not indicate which specific antigen-antibody incompatibility is implicated. The disorder in the fetus due to Rh D incompatibility is known as erythroblastosis fetalis.

Hemolytic comes from two words: "hemo" (blood) and "lysis" (destruction) or breaking down of red blood cells

Erythroblastosis refers to the making of immature red blood cells

Fetalis refers to the fetus.

When the condition is caused by the Rh D antigen-antibody incompatibility, it is called Rh D Hemolytic disease of the newborn (often called Rhesus disease or Rh disease for brevity). Here, sensitization to Rh D antigens (usually by feto-maternal transfusion during pregnancy) may lead to the production of maternal IgG anti-D antibodies which can pass through the placenta. This is of particular importance to D negative females at or below childbearing age, because any subsequent pregnancy may be affected by the Rhesus D hemolytic disease of the newborn if the baby is D positive. The vast majority of Rh disease is preventable in modern antenatal care by injections of IgG anti-D antibodies (Rho(D) Immune Globulin). The incidence of Rhesus disease is mathematically related to the frequency of D negative individuals in a population, so Rhesus disease is rare in East Asians, South Americans, and Africans, but more common in Caucasians.

Symptoms and signs in the fetus:

Enlarged liver, spleen, or heart and fluid buildup in the fetus' abdomen seen via ultrasound.

Symptoms and signs in the newborn:

Anemia that creates the newborn's pallor (pale appearance).

Jaundice or yellow discoloration of the newborn's skin, sclera or mucous membrane. This may be evident right after birth or after 24–48 hours after birth. This is caused by bilirubin (one of the end products of red blood cell destruction).

Enlargement of the newborn's liver and spleen.

The newborn may have severe edema of the entire body.

Dyspnea or difficulty breathing.

Population data

The frequency of Rh factor blood types and the RhD neg allele gene differs in various populations.

Population	Rh(D) Neg	Rh(D) Pos	Rh(D) Neg alleles
Basque people	21–36%[13]	65%	approx 60%
other Europeans	16%	84%	40%
African American	approx 7%	93%	approx 26%
Native Americans	approx 1%	99%	approx 10%
African descent	less 1%	over 99%	3%
Asian	less 1%	over 99%	1%

Inheritance

The D antigen is inherited as one gene (RHD) (on the short arm of the first chromosome, p36.13-p34.3) with various alleles. Though very much simplified, one can think of alleles that are positive or negative for the D antigen. The gene codes for the RhD protein on the red cell membrane. D- individuals who lack a functional RHD gene do not produce the D antigen, and may be immunized by D+ blood.

The epitopes for the next 4 most common Rh antigens, C, c, E and e are expressed on the highly similar RhCE protein that is genetically encoded in the RHCE gene. It has been shown that the RHD gene arose by duplication of the RHCE gene during primate evolution. Mice have just one RH gene.[14]

Function

The structure homology data suggested that the product of RHD gene, the RhD protein, acts as an membrane transport protein of uncertain specificity (CO2 or NH3) and unknown physiological role.[15][16] The three dimensional structure of the related RHCG protein and biochemical analysis of the RhD protein complex indicates that the RhD protein is one of three subunits of an ammonia transporter.[17][18] Three recent studies[19][20][21] have reported a protective effect of the RhD-positive phenotype, especially RhD heterozygosity, against the negative effect of latent toxoplasmosis on psychomotor performance in infected subjects. RhD-negative compared to RhD-positive subjects without anamnestic titres of anti-Toxoplasma antibodies have shorter reaction times in tests of simple reaction times. And conversely, RhD-negative subjects with anamnestic titres (i.e. with latent toxoplasmosis) exhibited much longer reaction times than their RhD-positive counterparts. The published data suggested that only the protection of RhD-positive heterozygotes was long term in nature; the protection of RhD-positive homozygotes decreased with duration of the infection while the performance of RhD-negative homozygotes decreased immediately after the infection.

Origin of RHD polymorphism

For a long time, the origin of RHD polymorphism was an evolutionary enigma.[22][23][24] Before the advent of modern medicine, the carriers of the rarer allele (e.g. RhD-negative women in a population of RhD positives or RhD-positive men in a population of RhD negatives) were at a disadvantage as some of their children (RhD-positive children born to preimmunised RhD-negative mothers) were at a higher risk of fetal or newborn death or health impairment from hemolytic disease. It was suggested that higher tolerance of RhD-positive heterozygotes against Toxoplasma-induced impairment of reaction time [19][20] and Toxoplasma-induced increase of risk of traffic accident[21] could counterbalance the disadvantage of the rarer allele and could be responsible both for the initial spread of the RhD allele among the RhD-negative population and for a stable RhD polymorphism in most human populations. It was also suggested that differences in the prevalence of Toxoplasma infection between geographical regions (0–95%) could also explain the striking variation in the frequency of RhD-negative alleles between populations. According to some parasitologists [19] it is possible that the better psychomotor performance of RhD-negative subjects in the Toxoplasma-free population could be the reason for spreading of the “d allele” (deletion) in the European population. In contrast to the situation in Africa and certain (but not all) regions of Asia, the abundance of wild cats (definitive hosts of Toxoplasma gondii) in Europe was very low before the advent of the domestic cat.

Weak D

In serologic testing, D positive blood is easily identified. Units which are D negative are often retested to rule out a weaker reaction. This was previously referred to as Du, which has been replaced.[25] By definition, weak D phenotype is characterized by negative reaction with anti-D reagent at immediate spin (IS), negative reaction after 37C incubation, and positive reaction at anti-human globulin (AHG) phase. Weak D phenotype can occur in several ways. In some cases, this phenotype occurs because of an altered surface protein that is more common in people of European descent. An inheritable form also occurs, most often in African-Americans, as a result of a weakened form of the R0 gene. Weak D may also occur as "C in trans," whereby a C gene is present on the opposite chromosome to a D gene (as in the combination R0r’, or "Dce/dCe"). The testing is difficult, since using different anti-D reagents, especially the older polyclonal reagents, may give different results.

The practical implication of this is that people with this sub-phenotype will have a product labeled as "D positive" when donating blood. When receiving blood, they are sometimes typed as a "D negative", though this is the subject of some debate. Most "Weak D" patients can receive "D positive" blood without complications.[26] However, it is important to correctly identify the ones that have to be considered D+ or D-. This is important, since most blood banks have a limited supply of "D negative" blood and the correct transfusion is clinically relevant. In this respect, genotyping of blood groups has much simplified this detection of the various variants in the Rh blood group system.

Other Rh group antigens

Currently, 50 antigens have been described in the Rh group system; among those described here, the D, C, c, E and e antigens are the most important. The others are much less frequently encountered or are rarely clinically significant. Each is given a number, though the highest assigned number (CEST or RH57 according to the ISBT terminology) is not an accurate reflection of the antigens encountered since many (e.g. Rh38) have been combined, reassigned to other groups, or otherwise removed.[27]

References

^ Levine P, Stetson RE (1939). "An unusual case of intragroup agglutination". JAMA 113: 126–7.

^ Landsteiner K, Wiener AS (1940). "An agglutinable factor in human blood recognized by immune sera for rhesus blood". Proc Soc Exp Biol Med 43: 223–4.

^ Landsteiner K, Wiener AS (1941). "Studies on an agglutinogen (Rh) in human blood reacting with anti-rhesus sera and with human isoantibodies". J Exp Med 74 (4): 309–320. doi:10.1084/jem.74.4.309. PMC 2135190. PMID 19871137. //www.ncbi.nlm.nih.gov/pmc/articles/PMC2135190/.

^ Avent ND, Reid ME (2000). "The Rh blood group system: a review". Blood 95 (2): 375–387. PMID 10627438.

^ Scott ML (2004). "The complexities of the Rh system". Vox sang 87 ((Suppl. 1)): S58–S62. doi:10.1111/j.1741-6892.2004.00431.x.

^ Weiner, Alexander S. (1 February 1949). "Genetics and Nomenclature of the Rh-Hr Blood Types". Antonie van Leeuwenhoek (Netherlands: Springerlink) 15 (1): 17–28. doi:10.1007/BF02062626. ISSN 0003-6072. http://www.springerlink.com/content/m4lg46567q12j8ul/. Retrieved 6 November 2010.

^ "dbRBC - Blood Group Antigen Gene Mutation Database". www.ncbi.nlm.nih.gov. http://www.ncbi.nlm.nih.gov/gv/mhc/xslcgi.cgi?cmd=bgmut/systems_info&system=rh. Retrieved 2010-06-15.

^ "RHD Rh blood group, D antigen [Homo sapiens - Gene Result"]. nlm.nih.gov. http://www.ncbi.nlm.nih.gov/sites/entrez?itool=omim_Detailed&DbFrom=omim&Cmd=Link&LinkName=omim_gene&IdsFromResult=111680. Retrieved 2010-06-15.

^ "RHCE Rh blood group, CcEe antigens [Homo sapiens - Gene Result"]. nlm.nih.gov. http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6006&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSum. Retrieved 2010-06-15.

^ Race, R.R.; A. A. Mourant, Sylvia D. Lawler and Ruth Sanger (1948). "The Rh Chromosome Frequencies in England". Blood (USA: American Society of Haematology) 3 (6): 689–695. PMID 18860341. http://bloodjournal.hematologylibrary.org/cgi/reprint/3/6/689.pdf. Retrieved 2010-11-14.

^ Canatan, Duran; Nilgün Acar &Banu Kiliç (1999). "Rh Subgroups and Kell Antigens in Patients With Thalassemia and in Donors in Turkey" (PDF). Turkish Journal of Medical Sciences (Tübitak) 29: 155–7. http://journals.tubitak.gov.tr/medical/issues/sag-99-29-2/sag-29-2-15-98073.pdf. Retrieved 2008-10-17.

^ Mack, Steve (March 21, 2001). "Re: Is the RH negative blood type more prevalent in certain ethnic groups?". MadSci Network. http://www.madsci.org/posts/archives/mar2001/985200157.Ge.r.html.

^ Touinssi, Mhammed; Chiaroni, Jacques; Degioanni, Anna; De Micco, Philippe; Dutour, Olivier; Bauduer, Frédéric (2004). "Distribution of rhesus blood group system in the French basques: a reappraisal using the allele-specific primers PCR method". Human Heredity 58 (2): 69–72. doi:10.1159/000083027. PMID 15711086.

^ Wagner FF, Flegel WA (Mar 2002). "RHCE represents the ancestral RH position, while RHD is the duplicated gene". Blood 99 (6): 2272–3. doi:10.1182/blood-2001-12-0153. PMID 11902138. http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=11902138.

^ Kustu S, Inwood W (2006). "Biological gas channels for NH3 and CO2: evidence that Rh (rhesus) proteins are CO2 channels". Transfusion Clinique et Biologique 13 (1-2): 103–110. doi:10.1016/j.tracli.2006.03.001. PMID 16563833.

^ Biver S, Scohy S, Szpirer J, Szpirer C, Andre B, Marini AM (2006). "Physiological role of the putative ammonium transporter RhCG in the mouse.". Transfusion Clinique et Biologique 13 (1-2): 167–8. doi:10.1016/j.tracli.2006.03.003. PMID 16564721.

^ Gruswitz, F.; Chaudhary, S.; Ho, J. D.; Schlessinger, A.; Pezeshki, B.; Ho, C. -M.; Sali, A.; Westhoff, C. M. et al. (2010). "Function of human Rh based on structure of RhCG at 2.1 A". Proceedings of the National Academy of Sciences 107 (21): 9638–9643. doi:10.1073/pnas.1003587107. PMC 2906887. PMID 20457942. //www.ncbi.nlm.nih.gov/pmc/articles/PMC2906887/. edit

^ Westhoff, C. M. (2007). "The Structure and Function of the Rh Antigen Complex". Seminars in Hematology 44 (1): 42–50. doi:10.1053/j.seminhematol.2006.09.010. PMC 1831834. PMID 17198846. //www.ncbi.nlm.nih.gov/pmc/articles/PMC1831834/. edit

^ a b c Novotna M, Havlicek J, Smith AP, Kolbekova P, Skallova A, Klose A, Gasova Z, Pisacka M, Sechovska M, Flegr J (2008). "Toxoplasma and reaction time: Role of toxoplasmosis in the origin, preservation and geographical distribution of Rh blood group polymorphism". Parasitology 135 (11): 1253–61. doi:10.1017/S003118200800485X. PMID 18752708. http://natur.cuni.cz/flegr/pdf/rh.pdf.

^ a b Flegr J, Novotna M, Lindova J, Havlicek J (2008). "Neurophysiological effect of the Rh factor. Protective role of the RhD molecule against Toxoplasma-induced impairment of reaction times in women". Neuroendocrinology Letters 29 (4): 475–481. PMID 18766148. http://natur.cuni.cz/flegr/pdf/rh2.pdf.

^ a b Flegr, J., Klose, J., Novotna, M., Berenreitterová, M. Havlicek, J. (2009). "Increased incidence of traffic accidents in Toxoplasma-infected military drivers and protective effect RhD molecule revealed by a large-scale prospective cohort study.". BMC Infect. Dis. 9: 72. doi:10.1186/1471-2334-9-72. PMC 2692860. PMID 19470165. http://www.biomedcentral.com/1471-2334/9/72.

^ Haldane JBF (1942). "Selection against heterozygosis in Man.". Eugenics 11: 333–340.

^ Fisher RA, Race RR, Taylor GL. (1944). "Mutation and the Rhesus reaction". Nature 153: 106. doi:10.1038/153106b0.

^ Li CC (1953). "Is the Rh facing a crossroad? A critique of the compensation effect.". Am Naturalist. 87: 257–261. doi:10.1086/281782.

^ Mark E. Brecher (2005). Technical Manual (15th ed.). Bethesda MD: American Association of Blood Banks. pp. 322. ISBN 1-56395-196-7.

^ Mark E. Brecher (2005). Technical Manual (15th ed.). Bethesda MD: American Association of Blood Banks. pp. 323. ISBN 1-56395-196-7.

^ Mark E. Brecher (2005). Technical Manual (15th ed.). Bethesda MD: American Association of Blood Banks. pp. 324. ISBN 1-56395-196-7.Population data for the Rh D factor and the RhD neg allele[12]Rh Phenotypes in Patients and Donors in Turkey[11]Rh phenotypes and genotypes

출처: http://en.wikipedia.org/wiki/Rh_blood_group_system

MNS antigen system

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The MNS antigen system is a human blood group system based upon two genes (glycophorin A and glycophorin B) on chromosome 4. There are currently 46 antigens in the system,[1] but the five most important are called M, N, S, s, and U.

The system can be thought of as two separate groups: the M and N antigens are at one location on the ECM and S, s, and U are on a closely related location. The two groups are very closely located together on chromosome 4 and are inherited as a haplotype.

Contents

1 The MN group

2 The U and Ss groups

3 Other MNS antigens

4 External links

5 References

The MN group

Main article: MN blood group

M+ and N+ RBCs are common (75% of population) and M+N+ cells are the most common genotype (50% of population). These antigens were an early discovery and are some of the oldest blood antigens known after the ABO system. They were first described by Karl Landsteiner and Philip Levine in 1927. Anti-M and anti-N antibodies are usually IgM and are rarely associated with transfusion reactions.

Anti-N is sometimes seen in dialysis patients due to cross-reactions with the residual formaldehyde from sterilizing the equipment. This is usually irrelevant for transfusion since this variant of the antibody does not react at body temperature.

The U and Ss groups

The S antigen is relatively common (~55% of the population) and the s antigen is very common (~89% of the population). Anti-S and anti-s can cause hemolytic transfusion reactions and hemolytic disease of the newborn.

The U antigen is a high incidence antigen, occurring in more than 99.9% of the population. The U was originally short for "Universal", though this is not the case. U negative RBCs can be found in people of African descent. This mutation in red cell surface structure also makes the RBCs S- and s-. Anti-U has been associated with both hemolytic transfusion reactions and hemolytic disease of the newborn.

Other MNS antigens

The other 41 identified antigens in the MNS group are low incidence, such as He (0.8% of the population) or high incidence, such as ENa (>99.9% of the population).

External links

MNS system at BGMUT Blood Group Antigen Gene Mutation Database, NCBI, NIH

References

Mark E. Brecher, Editor (2005), AABB Technical Manual, 15th edition, Bethesda, MD: AABB, ISBN 1-56395-196-7, p. 336-340

Denise M. Harmening (1999), Modern Blood Banking and Transfusion Practices, Philadelphia, PA: F.A. Davis Company, p. 164-169

^ ISBT Committee on Terminology for Red Cell Surface Antigens. "Table of blood group antigens within systems". International Society for Blood Transfusion. http://ibgrl.blood.co.uk/ISBTPages/ISBTTerminologyPages/Table%20of%20blood%20group%20antigens%20within%20systems.htm. Retrieved 2010-01-24.

출처: http://en.wikipedia.org/wiki/MNS_antigen_system

Kell blood group system, classification of human blood based on the presence on the surfaces of red blood cells of various antigens encoded by the KEL gene. The system, discovered in 1946, is characterized by a high degree of polymorphism (genetic variation), and thus studies of the Kell antigens have provided insight into the development of polymorphic traits in the context of human evolution. Antibodies generated against antigens in the Kell system can cause transfusion reactions and erythroblastosis fetalis; after the Rh and ABO systems, the Kell system is the third most common blood group to cause these reactions.

In total, there are 25 Kell antigens, all of which are encoded by the KEL gene. The two primary, codominant alleles of the KEL gene include K and k, which encode the K (Kell) and k (Cellano) antigens, respectively. The k antigen is common, occurring in more than 90 percent of blacks and whites. Polymorphisms in the KEL gene give rise to different antigens, including the Jsa and Jsb antigens. The Jsb antigen is found in 100 percent of whites and 80 percent of blacks. Examples of other Kell antigens include Kpa (Penney) and Kpb (Rautenberg).

Kell antigens normally associate with a protein called Kx on the surfaces of red blood cells. In some people, the Kx protein is absent, resulting in McLeod syndrome. Characteristics of this syndrome include acanthocytosis (thorny projections on red blood cells) and reduced Kell antigen expression. These abnormalities often lead to defects in muscle and nerve function that manifest as disordered movement, psychological disturbance, and loss of reflexes.

출처: http://www.britannica.com/EBchecked/topic/314337/Kell-blood-group-system

7.5 상염색체성 유전의 특징:Table 7.6

Haptoglobin

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Haptoglobin

Identifiers

Symbols

HP; BP; HP2ALPHA2; HPA1S

External IDs

OMIM: 140100 MGI: 96211 HomoloGene: 121756 GeneCards: HP Gene

[show]Gene Ontology
Molecular function	• catalytic activity • hemoglobin binding
Cellular component	• extracellular region • extracellular space • haptoglobin-hemoglobin complex
Biological process	• cellular iron ion homeostasis • defense response • positive regulation of cell death • response to hydrogen peroxide • negative regulation of oxidoreductase activity • negative regulation of hydrogen peroxide catabolic process
Sources: Amigo / QuickGO

RNA expression pattern

More reference expression data

Orthologs

Species

Human

Mouse

Entrez

3240

15439

Ensembl

ENSG00000257017

ENSMUSG00000031722

UniProt

P00738

Q61646

RefSeq (mRNA)

NM_001126102.1

NM_017370.2

RefSeq (protein)

NP_001119574.1

NP_059066.1

Location (UCSC)

Chr 16:
72.09 – 72.09 Mb

Chr 8:
109.58 – 109.58 Mb

PubMed search

[1]

[2]

This box:

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A model of α,β-hemoglobin/haptoglobin hexamer complex

Haptoglobin (abbreviated as Hp) is the protein that in humans is encoded by the HP gene.[1][2] In blood plasma, haptoglobin binds free hemoglobin (Hb) released from erythrocytes with high affinity and thereby inhibits its oxidative activity. The haptoglobin-hemoglobin complex will then be removed by the reticuloendothelial system (mostly the spleen). In clinical settings, the haptoglobulin assay is used to screen for and monitor intravascular hemolytic anemia . In intravascular hemolysis, free hemoglobin will be released into circulation and hence haptoglobin will bind the Hb. This causes a decline in Hp levels. Conversely, in extravascular hemolysis the reticuloendothelial system, especially splenic monocytes, phagocytose the erythrocytes and hemoglobin is not released into circulation; serum haptoglobin levels are therefore normal.

Contents

1 Function

2 Synthesis

3 Structure

4 In other species

5 Clinical significance

5.1 Test protocol

5.2 Interpretation

6 References

7 Further reading

8 External links

Function

This gene encodes a preproprotein that is processed to yield both alpha and beta chains, which subsequently combine as a tetramer to produce haptoglobin. Haptoglobin functions to bind free plasma hemoglobin, which allows degradative enzymes to gain access to the hemoglobin while at the same time preventing loss of iron through the kidneys and protecting the kidneys from damage by hemoglobin.[3] For this reason it is often referred to as the suicide protein.

Synthesis

Haptoglobin is produced mostly by hepatocytes but also by other tissues: e.g., skin, lung, and kidney. In addition, the haptoglobin gene is expressed in murine and human adipose tissue.[4]

Haptoglobin had been shown to be expressed in adipose tissue of cattle as well. [5]

Structure

Haptoglobin, in its simplest form, consists of two α- and two β-chains, connected by disulfide bridges. The chains originate from a common precursor protein, which is proteolytically cleaved during protein synthesis.

Hp exists in two allelic forms in the human population, so-called Hp1 and Hp2, the latter one having arisen due to the partial duplication of Hp1 gene. Three genotypes of Hp, therefore, are found in humans: Hp1-1, Hp2-1, and Hp2-2. Hp of different genotypes have been shown to bind hemoglobin with different affinities, with Hp2-2 being the weakest binder.

In other species

Hp has been found in all mammals studied so far, some birds, e.g., cormorant and ostrich but also, in its simpler form, in bony fish, e.g., zebrafish. It is interesting to note that Hp is absent in at least some amphibians (Xenopus) and neognathous birds (chicken and goose).

Clinical significance

Mutations in this gene and/or its regulatory regions cause ahaptoglobinemia or hypohaptoglobinemia. This gene has also been linked to diabetic nephropathy,[6] the incidence of coronary artery disease in type 1 diabetes,[7] Crohn's disease,[8] inflammatory disease behavior, primary sclerosing cholangitis, susceptibility to idiopathic Parkinson's disease,[9] and a reduced incidence of Plasmodium falciparum malaria.[10]

Since the reticuloendothelial system will remove the haptoglobin-hemoglobin complex from the body, haptoglobin levels will be decreased in hemolytic anemias. In the process of binding hemoglobin, haptoglobin sequesters the iron within hemoglobin, preventing iron-utilizing bacteria from benefiting from hemolysis. It is theorized that, because of this, haptoglobin has evolved into an acute-phase protein. HP has a protective influence on the hemolytic kidney.[11][12]

Some studies associate certain haptoglobin phenotypes with the risk of developing schizophrenia.[13]

Test protocol

Haptoglobin is ordered whenever a patient exhibits symptoms of anemia, such as pallor, fatigue, or shortness of breath, along with physical signs of hemolysis, such as jaundice or dark-colored urine. The test is also commonly ordered as a hemolytic anemia battery, which also includes a reticulocyte count and a peripheral blood smear. It can also be ordered along with a Direct Antiglobulin Test when a patient is suspected of having a transfusion reaction or symptoms of autoimmune hemolytic anemia. Also, it may be ordered in conjunction with a bilirubin.

Interpretation

A decrease in haptoglobin can support a diagnosis of hemolytic anemia, especially when correlated with a decreased RBC count, hemoglobin, and hematocrit, and also an increased reticulocyte count.

If the reticulocyte count is increased, but the haptoglobin level is normal, this may indicate that cellular destruction is occurring in the spleen and liver, which may indicate a drug-induced hemolysis, or a red cell dysplasia. The spleen and liver recognize an error in the red cells (either Drug coating the red cell membrane or a dysfunctional red cell membrane), and destroy the cell. This type of destruction does not release hemoglobin into the peripheral blood, so the haptoglobin cannot bind to it. Thus, the haptoglobin will stay normal if the hemolysis is not severe. In severe extra-vascular hemolysis, haptoglobin levels can also be low, when large amount of hemoglobin in the reticuloendothelial system leads to transfer of free hemoglobin into plasma.[14]

If there are symptoms of anemia but both the reticulocyte count and the haptoglobin level are normal, the anemia is most likely not due to hemolysis, but instead some other error in cellular production, such as aplastic anemia

Haptoglobin levels that are decreased but do not accompany signs of anemia may indicate liver damage, as the liver is not producing enough haptoglobin to begin with.

As haptoglobin is indeed an acute-phase protein, any inflammatory process (infection, extreme stress, burns, major crush injury, allergy, etc.) may increase the levels of plasma haptoglobin.

References

^ Dobryszycka W (September 1997). "Biological functions of haptoglobin--new pieces to an old puzzle". Eur J Clin Chem Clin Biochem 35 (9): 647–54. PMID 9352226.

^ Wassell J (2000). "Haptoglobin: function and polymorphism". Clin. Lab. 46 (11–12): 547–52. PMID 11109501.

^ "Entrez Gene: HP". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3240.

^ Trayhurn P, Wood IS (September 2004). "Adipokines: inflammation and the pleiotropic role of white adipose tissue". Br. J. Nutr. 92 (3): 347–55. doi:10.1079/BJN20041213. PMID 15469638.

^ Saremi B, Al-Dawood A, Winand S, Müller U, Pappritz J, von Soosten D, Rehage J, Dänicke S, Häussler S, Mielenz M, Sauerwein H. (May 2012). "Bovine haptoglobin as an adipokine: Serum concentrations and tissue expression in dairy cows receiving a conjugated linoleic acids supplement throughout lactation". Vet Immunol Immunopathol. 146 (3-4): 201–11. doi:10.1016/j.vetimm.2012.03.011. PMID 22498004.

^ Asleh R, Levy AP (2005). "In vivo and in vitro studies establishing haptoglobin as a major susceptibility gene for diabetic vascular disease". Vasc Health Risk Manag 1 (1): 19–28. doi:10.2147/vhrm.1.1.19.58930. PMC 1993923. PMID 17319095. //www.ncbi.nlm.nih.gov/pmc/articles/PMC1993923/.

^ Sadrzadeh SM, Bozorgmehr J (June 2004). "Haptoglobin phenotypes in health and disorders". Am. J. Clin. Pathol. 121 Suppl: S97–104. PMID 15298155.

^ Papp M, Lakatos PL, Palatka K, Foldi I, Udvardy M, Harsfalvi J, Tornai I, Vitalis Z, Dinya T, Kovacs A, Molnar T, Demeter P, Papp J, Lakatos L, Altorjay I (May 2007). "Haptoglobin polymorphisms are associated with Crohn's disease, disease behavior, and extraintestinal manifestations in Hungarian patients". Dig. Dis. Sci. 52 (5): 1279–84. doi:10.1007/s10620-006-9615-1. PMID 17357835.

^ Costa-Mallen P, Checkoway H, Zabeti A, Edenfield MJ, Swanson PD, Longstreth WT, Franklin GM, Smith-Weller T, Sadrzadeh SM (March 2008). "The functional polymorphism of the hemoglobin-binding protein haptoglobin influences susceptibility to idiopathic Parkinson's disease". Am. J. Med. Genet. B Neuropsychiatr. Genet. 147B (2): 216–22. doi:10.1002/ajmg.b.30593. PMID 17918239.

^ Prentice AM, Ghattas H, Doherty C, Cox SE (December 2007). "Iron metabolism and malaria". Food Nutr Bull 28 (4 Suppl): S524–39. PMID 18297891.

^ Pintera J (1968). "The protective influence of haptoglobin on hemoglobinuric kidney. I. Biochemical and macroscopic observations". Folia Haematol. Int. Mag. Klin. Morphol. Blutforsch. 90 (1): 82–91. PMID 4176393.

^ Miederer SE, Hotz J (December 1969). "[Pathogenesis of kidney hemolysis]" (in German). Bruns Beitr Klin Chir 217 (7): 661–5. PMID 5404273.

^ Gene Overview of All Published Schizophrenia-Association Studies for HP - SzGene database at Schizophrenia Research Forum.

^ Temple, Victor. "HEMOLYSIS AND JAUNDICE: An overview". http://www.victorjtemple.com/pbl-Haelysis%20and%20Jaunidce.pdf. Retrieved 9 July 2011.

출처: http://en.wikipedia.org/wiki/Haptoglobin

Human leukocyte antigen

HLA region of Chromosome 6

The human leukocyte antigen (HLA) system is the name of the major histocompatibility complex (MHC) in humans. The super locus contains a large number of genes related to immune system function in humans. This group of genes resides on chromosome 6, and encodes cell-surface antigen-presenting proteins and has many other functions. The HLA genes are the human versions of the MHC genes that are found in most vertebrates (and thus are the most studied of the MHC genes). The proteins encoded by certain genes are also known as antigens, as a result of their historic discovery as factors in organ transplants. The major HLA antigens are essential elements for immune function. Different classes have different functions:

HLAs corresponding to MHC class I (A, B, and C) present peptides from inside the cell (including viral peptides if present). These peptides are produced from digested proteins that are broken down in the proteasomes. In general, the peptides are small polymers, about 9 amino acids in length. Foreign antigens attract killer T-cells (also called CD8 positive- or cytotoxic T-cells) that destroy cells.

HLAs corresponding to MHC class II (DP, DM, DOA, DOB, DQ, and DR) present antigens from outside of the cell to T-lymphocytes. These particular antigens stimulate the multiplication of T-helper cells, which in turn stimulate antibody-producing B-cells to produce antibodies to that specific antigen. Self-antigens are suppressed by suppressor T-cells.

HLAs corresponding to MHC class III encode components of the complement system.

HLAs have other roles. They are important in disease defense. They are the major cause of organ transplant rejections. They may protect against or fail to protect (if down regulated by an infection) against cancers.[1] Mutations in HLA may be linked to autoimmune disease (examples: type I diabetes, coeliac disease). HLA may also be related people's perception of the odor of other people, and may be involved in mate selection, as at least one study found a lower than expected rate of HLA similarity between spouses in an isolated community.[2]

Aside from the genes encoding the 6 major antigen-presenting proteins, there are a large number of other genes, many involved in immune function, located on the HLA complex. Diversity of HLAs in the human population is one aspect of disease defense, and, as a result, the chance of two unrelated individuals with identical HLA molecules on all loci is very low. HLA genes have historically been identified as a result of the ability to successfully transplant organs between HLA-similar individuals.

Contents

1 Functions

1.1 In infectious disease

1.2 In graft rejection

1.3 In autoimmunity

1.4 In cancer

2 Classification

2.1 Nomenclature

2.2 Variability

2.2.1 Tables of variant alleles

2.2.2 Sequence Feature Variant Type (SFVT)

2.3 Examining HLA types

2.3.1 Serotype and allele names

2.3.2 Serotyping

2.3.3 Cellular typing

2.3.4 Gene sequencing

2.3.5 Phenotyping

2.3.6 Haplotypes

3 Role of allelic variation

4 Antibodies

5 HLA matching for sick siblings

6 See also

7 Further reading

8 External links

9 References

Functions

The proteins encoded by HLAs are those on the outer part of body cells that are (effectively) unique to that person. The immune system uses the HLAs to differentiate self cells and non-self cells. Any cell displaying that person's HLA type belongs to that person and therefore is not an invader.

DR protein (DRA:DRB1*0101 gene products) with bound Staphylococcal enterotoxin ligand (subunit I-C), view is top down showing all DR amino acid residues within 5 Angstroms of the SEI peptide. PDB [http://www.rcsb.org/pdb/explore/explore.do?structureId=2G9H 2G9H

]

In infectious disease

When a foreign pathogen enters the body, specific cells called antigen-presenting cells (APCs) engulf the pathogen through a process called phagocytosis. Proteins from the pathogen are digested into small pieces (peptides) and loaded onto HLA antigens (to be specific, MHC class II). They are then displayed by the antigen-presenting cells to T cells, which then produce a variety of effects to eliminate the pathogen.

Through a similar process, proteins (both native and foreign, such as the proteins of virus) produced inside most cells are displayed on HLAs (to be specific, MHC class I) on the cell surface. Infected cells can be recognized and destroyed by CD8+ T cells.

The image off to the side shows a piece of a poisonous bacterial protein (SEI peptide) bound within the binding cleft portion of the HLA-DR1 molecule. In the illustration far below, a different view, one can see an entire DQ with a bound peptide in a similar cleft, as viewed from the side. Disease-related peptides fit into these "slots" much like a hand fits into a glove. When bound, peptides are presented to T cells. T cells require presentation via MHC molecules to recognize foreign antigens — a requirement known as MHC restriction. These cells have receptors that are similar to B cell receptors, and each cell recognizes only a few class II-peptide combinations. Once a T cell recognizes a peptide within an MHC class II molecule, it can stimulate B-cells that also recognize the same molecule in their B cell receptors. Thus, T cells help B cells make antibodies to the same foreign antigens. Each HLA can bind many peptides, and each person has 3 HLA types and can have 4 isoforms of DP, 4 isoforms of DQ and 4 Isoforms of DR (2 of DRB1, and 2 of DRB3,DRB4, or DRB5) for a total of 12 isoforms. In such heterozygotes, it is difficult for disease-related proteins to escape detection.

In graft rejection

Any cell displaying some other HLA type is "non-self" and is seen as an invader by the body's immune system, resulting in the rejection of the tissue bearing those cells. This is particularly important in the case of transplanted tissue, because it could lead to transplant rejection. Because of the importance of HLA in transplantation, the HLA loci are some of the most frequently typed by serology and PCR.

HLA allele	Diseases with increased risk	Relative risk
HLA-B27	Ankylosing spondylitis	12[3]
	Postgonococcal arthritis	14[3]
	Acute anterior uveitis	15[3]
HLA-B47	21-hydroxylase deficiency	15[3]
HLA-DR2	Systemic lupus erythematosus	2 to 3[4]
HLA-DR3	Autoimmune hepatitis	14[3]
	Primary Sjögren syndrome	10[3]
	Diabetes mellitus type 1	5[3]
	Systemic lupus erythematosus	2 to 3[4]
HLA-DR4	Rheumatoid arthritis	4[3]
	Diabetes mellitus type 1	6[3]
HLA-DR3 and -DR4 combined	Diabetes mellitus type 1	15[3]

In autoimmunity

HLA types are inherited, and some of them are connected with autoimmune disorders and other diseases. People with certain HLA antigens are more likely to develop certain autoimmune diseases, such as type I diabetes, ankylosing spondylitis, celiac disease, SLE (systemic lupus erythematosus), myasthenia gravis, inclusion body myositis, and Sjögren syndrome. HLA typing has led to some improvement and acceleration in the diagnosis of celiac disease and type 1 diabetes; however, for DQ2 typing to be useful, it requires either high-resolution B1*typing (resolving *02:01 from *02:02), DQA1*typing, or DR serotyping. Current serotyping can resolve, in one step, DQ8. HLA typing in autoimmunity is being increasingly used as a tool in diagnosis. In celiac disease, it is the only effective means of discriminating between first-degree relatives that are at risk from those that are not at risk, prior to the appearance of sometimes-irreversible symptoms such as allergies and secondary autoimmune disease.

In cancer

Some HLA-mediated diseases are directly involved in the promotion of cancer. Gluten-sensitive enteropathy is associated with increased prevalence of enteropathy-associated T-cell lymphoma, and DR3-DQ2 homozygotes are within the highest risk group, with close to 80% of gluten-sensitive enteropathy-associated T-cell lymphoma cases. More often, however, HLA molecules play a protective role, recognizing increases in antigens that are not tolerated because of low levels in the normal state. Abnormal cells might be targeted for apoptosis, which is thought to mediate many cancers before diagnosis.

Classification

Schematic representation of MHC class I

MHC class I proteins form a functional receptor on most nucleated cells of the body.

There are 3 major and 3 minor MHC class I genes in HLA:

HLA-A

HLA-B

HLA-C

minor genes are HLA-E, HLA-F and HLA-G

β2-microglobulin binds with major and minor gene subunits to produce a heterodimer

Illustration of an HLA-DQ molecule (magenta and blue) with a bound ligand (yellow) floating on the plasma membrane of the cell.

There are 3 major and 2 minor MHC class II proteins encoded by the HLA. The genes of the class II combine to form heterodimeric (αβ) protein receptors that are typically expressed on the surface of antigen-presenting cells.

Major MHC class II

HLA-DP

α-chain encoded by HLA-DPA1 locus

β-chain encoded by HLA-DPB1 locus

HLA-DQ

α-chain encoded by HLA-DQA1 locus

β-chain encoded by HLA-DQB1 locus

HLA-DR

α-chain encoded by HLA-DRA locus

4 β-chains (only 3 possible per person), encoded by HLA-DRB1, DRB3, DRB4, DRB5 loci

The other MHC class II proteins, DM and DO, are used in the internal processing of antigens, loading the antigenic peptides generated from pathogens onto the HLA molecules of antigen-presenting cell.

Nomenclature

Modern HLA alleles are typically noted with a variety of levels of detail. Most designations begin with HLA- and the locus name, then * and some (even) number of digits specifying the allele. The first two digits specify a group of alleles. Older typing methodologies often could not completely distinguish alleles and so stopped at this level. The third through fourth digits specify a synonymous allele. Digits five through six denote any synonymous mutations within the coding frame of the gene. The seventh and eighth digits distinguish mutations outside the coding region. Letters such as L, N, Q, or S may follow an allele's designation to specify an expression level or other non-genomic data known about it. Thus, a completely described allele may be up to 9 digits long, not including the HLA-prefix and locus notation.

Further information: History and naming of human leukocyte antigens

Variability

Codominant expression of HLA genes.

MHC loci are some of the most genetically variable coding loci in mammals, and the human HLA loci are no exceptions. Despite the fact that the human population went through a constriction more than 150 000 years ago that was capable of fixing many loci, the HLA loci appear to have survived such a constriction with a great deal of variation.[5] Of the 9 loci mentioned above, most retained a dozen or more allele-groups for each locus, far more preserved variation than the vast majority of human loci. This is consistent with a heterozygous or balancing selection coefficient for these loci. In addition, some HLA loci are among the fastest-evolving coding regions in the human genome. One mechanism of diversification has been noted in the study of Amazonian tribes of South America that appear to have undergone intense gene conversion between variable alleles and loci within each HLA gene class.[6] Less frequently, longer-range productive recombinations through HLA genes have been noted producing chimeric genes.

Six loci have over 100 alleles that have been detected in the human population. Of these, the most variable are HLA B and HLA DRB1. As of 2012, the number of alleles that have been determined are listed in the table below. To interpret this table, it is necessary to consider that an allele is a variant of the nucleotide (DNA) sequence at a locus, such that each allele differs from all other alleles in at least one (single nucleotide polymorphism, SNP) position. Most of these changes result in a change in the amino acid sequences that result in slight to major functional differences in the protein.

There are issues that limit this variation. Certain alleles like DQA1*05:01 and DQA1*05:05 encode proteins with identically processed products. Other alleles like DQB1*0201 and DQB1*0202 produce proteins that are functionally similar. For class II (DR, DP and DQ), amino acid variants within the receptor's peptide-binding cleft tend to produce molecules with different binding capability.

Tables of variant alleles

Number of variant alleles at class I loci according to the IMGT-HLA database, last updated June 2012:

MHC class I
locus	#[7][8]
Major Antigens
HLA A	1,884
HLA B	2,490
HLA C	1,384
Minor Antigens
HLA E	11
HLA F	22
HLA G	49

Number of variant alleles at class II loci (DM, DO, DP, DQ, and DR):

MHC class II
HLA	-A1	-B1	-B3 to -B51	Theor. possible
locus	#[8]	#[8]	#[8]	combinations
DM-	7	13		91
DO-	12	13		156
DP-	34	155		5,270
DQ-	47	165		7,755
DR-	7	1,094	92	8,302
1DRB3, DRB4, DRB5 have variable presence in humans

Sequence Feature Variant Type (SFVT)

The large extent of variability in HLA genes poses significant challenges in investigating the role of HLA genetic variations in diseases. Disease association studies typically treat each HLA allele as a single complete unit, which does not illuminate the parts of the molecule associated with disease. Karp D. R. et al. describes a novel Sequence Feature Variant Type (SFVT) approach for HLA genetic analysis that categorizes HLA proteins into biologically relevant smaller sequence features (SFs), and their variant types (VTs).[9] Sequence features are combinations of amino acid sites defined based on structural information (e.g., beta-sheet 1), functional information (e.g., peptide antigen-binding), and polymorphism. These sequence features can be overlapping and continuous or discontinuous in the linear sequence. Variant types for each sequence feature are defined based upon all known polymorphisms in the HLA locus being described. SFVT categorization of HLA is applied in genetic association analysis so that the effects and roles of the epitopes shared by several HLA alleles can be identified. Sequence features and their variant types have been described for all classical HLA proteins; the international repository of HLA SFVTs will be maintained at IMGT/HLA database.[10] A tool to convert HLA alleles into their component SFVTs can be found on the Immunology Database and Analysis Portal (ImmPort) website.[11]

Examining HLA types

Serotype and allele names

There are two parallel systems of nomenclature that are applied to HLA. The, first, and oldest system is based on serological (antibody based) recognition. In this system, antigens were eventually assigned letters and numbers (e.g., HLA-B27 or, shortened, B27). A parallel system that allowed more refined definition of alleles was developed. In this system, a "HLA" is used in conjunction with a letter * and four-or-more-digit number (e.g., HLA-B*08:01, A*68:01, A*24:02:01N N=Null) to designate a specific allele at a given HLA locus. HLA loci can be further classified into MHC class I and MHC class II (or rarely, D locus). Every two years, a nomenclature is put forth to aid researchers in interpreting serotypes to alleles.[7]

Serotyping

Further information: Serotype

In order to create a typing reagent, blood from animals or humans would be taken, the blood cells allowed to separate from the serum, and the serum diluted to its optimal sensitivity and used to type cells from other individuals or animals. Thus, serotyping became a way of crudely identifying HLA receptors and receptor isoforms. Over the years, serotyping antibodies became more refined as techniques for increasing sensitivity improved and new serotyping antibodies continue to appear. One of the goals of serotype analysis is to fill gaps in the analysis. It is possible to predict based on 'square root','maximum-likelihood' method, or analysis of familial haplotypes to account for adequately typed alleles. These studies using serotyping techniques frequently revealed, in particular for non-European or north East Asian populations a large number of null or blank serotypes. This was particularly problematic for the Cw locus until recently, and almost half of the Cw serotypes went untyped in the 1991 survey of the human population.

There are several types of serotypes. A broad antigen serotype is a crude measure of identity of cells. For example, HLA A9 serotype recognizes cells of A23- and A24-bearing individuals. It may also recognize cells that A23 and A24 miss because of small variations. A23 and A24 are split antigens, but antibodies specific to either are typically used more often than antibodies to broad antigens.

Cellular typing

A representative cellular assay is the mixed lymphocyte culture (MLC) and used to determine the HLA class II types.[12] The cellular assay is more sensitive in detecting HLA differences than serotyping. This is because minor differences unrecognized by alloantisera can stimulate T cells. This typing is designated as Dw types. Serotyped DR1 has cellularly defined as either of Dw1 or of Dw20 and so on for other serotyped DRs. Table[13] shows associated cellular specificities for DR alleles. However, cellular typing has inconsistence in the reaction between cellular-type individuals, sometimes resulting differently from predicted. Together with difficulty of cellular assay in generating and maintaining cellular typing reagents, cellular assay is being replaced by DNA-based typing method.[12]

Gene sequencing

Minor reactions to subregions that show similarity to other types can be observed to the gene products of alleles of a serotype group. The sequence of the antigens determines the antibody reactivities, and so having a good sequencing capability (or sequence-based typing) obviates the need for serological reactions. Therefore, different serotype reactions may indicate the need to sequence a person's HLA to determine a new gene sequence. Broad antigen types are still useful, such as typing very diverse populations with many unidentified HLA alleles (Africa, Arabia,[14] Southeastern Iran[15] and Pakistan, India[16]). Africa, Southern Iran, and Arabia show the difficulty in typing areas that were settled earlier. Allelic diversity makes it necessary to use broad antigen typing followed by gene sequencing because there is an increased risk of misidentifying by serotyping techniques.

In the end, a workshop, based on sequence, decides which new allele goes into which serogroup either by sequence or by reactivity. Once the sequence is verified, it is assigned a number. For example, a new allele of B44 may get a serotype B*44:65, as it is the 65th B44 allele discovered. Marsh et al. (2005)[7] can be considered a code book for HLA serotypes and genotypes, and a new book biannually with monthly updates in Tissue Antigens.

Phenotyping

Gene typing is different from gene sequencing and serotyping. With this strategy, PCR primers specific to a variant region of DNA are used (called SSP-PCR). If a product of the right size is found, the assumption is that the HLA allele has been identified. New gene sequences often result in an increasing appearance of ambiguity. Because gene typing is based on SSP-PCR, it is possible that new variants, in particular in the class I and DRB1 loci, may be missed.

For example, SSP-PCR within the clinical situation is often used for identifying HLA phenotypes. An example of an extended phenotype for a person might be:

A*01:01/*03:01, C*07:01/*07:02, B*07:02/*08:01, DRB1*03:01/*15:01, DQA1*05:01/*01:02, DQB1*02:01/*06:02

In general, this is identical to the extended serotype: A1,A3,B7,B8,DR3,DR15(2), DQ2,DQ6(1)

For many populations, such as the Japanese or European populations, so many patients have been typed that new alleles are relatively rare, and thus SSP-PCR is more than adequate for allele resolution. Haplotypes can be obtained by typing family members in areas of the world where SSP-PCR is unable to recognize alleles and typing requires the sequencing of new alleles. Areas of the world were SSP-PCR or serotyping may be inadequate include Central Africa, Eastern Africa, parts of southern Africa, Arabia, S. Iran, Pakistan, and India.

Haplotypes

An HLA haplotype is a series of HLA "genes" (loci-alleles) by chromosome, one passed from the mother and one from the father.

The phenotype exampled above is one of the more common in Ireland and is the result of two common genetic haplotypes:

A*01:01 ; C*07:01 ; B*08:01 ; DRB1*03:01 ; DQA1*05:01 ; DQB1*02:01 (By serotyping A1-Cw7-B8-DR3-DQ2)

which is called ' 'super B8' ' or ' 'ancestral haplotype' ' and

A*03:01 ; C*07:02 ; B*07:02 ; DRB1*15:01 ; DQA1*01:02 ; DQB1*06:02 (By serotyping A3-Cw7-B7-DR15-DQ6 or the older version "A3-B7-DR2-DQ1")

These haplotypes can be used to trace migrations in the human population because they are often much like a fingerprint of an event that has occurred in evolution. The Super-B8 haplotype is enriched in the Western Irish, declines along gradients away from that region, and is found only in areas of the world where Western Europeans have migrated. The "A3-B7-DR2-DQ1" is more widely spread, from Eastern Asia to Iberia. The Super-B8 haplotype is associated with a number of diet-associated autoimmune diseases. There are 100,000s of extended haplotypes, but only a few show a visible and nodal character in the human population.

Role of allelic variation

Studies of humans and other animals imply a heterozygous selection mechanism operating on these loci as an explanation for this exceptional variability.[17] One credible mechanism is sexual selection in which females are able to detect males with different HLA relative to their own type.[18] While the DQ and DP encoding loci have fewer alleles, combinations of A1:B1 can produce a theoretical potential of 7,755 DQ and 5,270 DP αβ heterodimers, respectively. While nowhere near this number of isoforms exist in the human population, each individual can carry 4 variable DQ and DP isoforms, increasing the potential number of antigens that these receptors can present to the immune system in individual immune system. Studies of the variable positions of DP, DR, and DQ reveal that peptide antigen contact residues on class II molecules are most frequently the site of variation in the protein primary structure. Therefore, through a combination of intense allelic variation and/or subunit pairing, the class II 'peptide' receptors are capable of binding an almost endless variation of peptides of 9 amino acids or longer in length, protecting interbreeding subpopulations from nascent or epidemic diseases. Individuals in a population frequently have different haplotypes, and this results in many combinations, even in small groups. This diversity enhances the survival of such groups, and thwarts evolution of epitopes in pathogens, which would otherwise be able to be shielded from the immune system.

Antibodies

HLA antibodies are typically not naturally occurring, with few exceptions are formed as a result of an immunologic challenge of a foreign material containing non-self HLAs via blood transfusion, pregnancy (paternally-inherited antigens), or organ or tissue transplant.

Antibodies against disease-associated HLA haplotypes have been proposed as a treatment for severe autoimmune diseases.[19]

Donor-specific HLA antibodies have been found to be associated with graft failure in kidney, heart, lung, and liver transplantation.

HLA matching for sick siblings

Main article: Savior sibling

In some diseases requiring hematopoietic stem cell transplantation, preimplantation genetic diagnosis may be used to give rise to a sibling with matching HLA, although there are ethical considerations.[20]

See also

HCP5

List of human leukocyte antigen alleles associated with cutaneous conditions

Further reading

Harsanyi, Zsolt; Hutton, Richard (1982). Genetic Prophecy: Beyond the Double Helix. London: Granada. ISBN 0-246-11760-5

External links

IMGT/HLA Sequence Database at European Bioinformatics Institute

hla.alleles.org

HLA Informatics Group at The Anthony Nolan Trust

British Society for Histocompatibility and Immunogenetics

American Society for Histocompatibility and Immunogenetics

European Federation for Immunogenetics

HistoCheck HLA matching tool for organ and stem cell transplantation

Allele Frequencies at Variable Immune related loci

Human+leukocyte+antigens at the US National Library of Medicine Medical Subject Headings (MeSH)

dbMHC Home, NCBI's database of the Major Histocompatibility Complex

References

^ Galbraith, W; Wagner, MC; Chao, J; Abaza, M; Ernst, LA; Nederlof, MA; Hartsock, RJ; Taylor, DL et al. (1991). "Imaging cytometry by multiparameter fluorescence.". Cytometry 12 (7): 579–96. doi:10.1002/cyto.990120702. PMID 1782829.

^ Brennan, P; Kendrick, K (2006). "Mammalian social odours: attraction and individual recognition". Philos Trans R Soc Lond B Biol Sci 361 (1476): 2061–78. doi:10.1098/rstb.2006.1931. PMC 1764843. PMID 17118924. //www.ncbi.nlm.nih.gov/pmc/articles/PMC1764843/.

^ a b c d e f g h i j Table 5-7 in: Mitchell, Richard Sheppard; Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson (2007). Robbins Basic Pathology. Philadelphia: Saunders. ISBN 1-4160-2973-7. 8th edition.

^ a b Values are given for Caucasians, according to Page 61 (right column) in: Jane Salmon; Wallace, Daniel J.; Dubois, Edmund L.; Kirou, Kyriakos A.; Hahn, Bevra; Lehman, Thomas A. (2007). Dubois' lupus erythematosus. Philadelphia: Lippincott Williams &Wilkin. ISBN 0-7817-9394-7.

^ Shennan, Douglas H (2006). Evolution and the Spiral of Technology. Trafford Publishing. ISBN 1-55212-518-1.

^ P. Parham and T. Ohta (1996). "Population Biology of Antigen Presentation by MHC class I Molecules". Science 272 (5258): 67–74. doi:10.1126/science.272.5258.67. PMID 8600539..

^ a b c Marsh SG, Albert ED, Bodmer WF, Bontrop RE, Dupont B, Erlich HA, Geraghty DE, Hansen JA, Hurley CK, Mach B, Mayr WR, Parham P, Petersdorf EW, Sasazuki T, Schreuder GM, Strominger JL, Svejgaard A, Terasaki PI, and Trowsdale J. (2005). "Nomenclature for factors of the HLA System, 2004". Tissue Antigens 65 (4): 301–369. doi:10.1111/j.1399-0039.2005.00379.x. PMID 15787720.

^ a b c d IMGT/HLA Database

^ Karp DR, Marthandan N, Marsh SG, Ahn C, Arnett FC, Deluca DS, Diehl AD, Dunivin R, Eilbeck K, Feolo M, Guidry PA, Helmberg W, Lewis S, Mayes MD, Mungall C, Natale DA, Peters B, Petersdorf E, Reveille JD, Smith B, Thomson G, Waller MJ, and Scheuermann RH. (2010). "Novel sequence feature variant type analysis of the HLA genetic association in systemic sclerosis". Human Molecular Genetics 19 (4): 707–719. doi:10.1093/hmg/ddp521. PMC 2807365. PMID 19933168. //www.ncbi.nlm.nih.gov/pmc/articles/PMC2807365/.

^ "IMGT/HLA Database". http://www.ebi.ac.uk/imgt/hla/.

^ "Immunology Database and Analysis Portal (ImmPort)". https://www.immport.org/immportWeb/home/home.do?loginType=full.

^ a b Hurley CK (1997). "DNA-based typing of HLA for transplantation." In Leffell MS, Donnenberg AD, Rose NR, eds. (1997) Handbook of Human Immunology. pp. 521-55, Boca Raton: CRC Press, ISBN 0-8493-0134-3.

^ Bodmer, JG; Marsh, SG; Albert, ED; Bodmer, WF; Dupont, B; Erlich, HA; Mach, B; Mayr, WR et al. (1992). "Nomenclature for factors of the HLA system, 1991". Human immunology 34 (1): 4–18. doi:10.1016/0198-8859(92)90079-3. PMID 1399721.

^ Valluri V, Mustafa M, Santhosh A, Middleton D, Alvares M, El Haj E, Gumama O, and Abdel-Wareth L (2005). "Frequencies of HLA-A, HLA-B, HLA-DR, and HLA-DQ phenotypes in the United Arab Emirates population". Tissue Antigens 66 (2): 107–113. doi:10.1111/j.1399-0039.2005.00441.x. PMID 16029430.

^ Farjadian S, Naruse T, Kawata H, Ghaderi A, Bahram S, and Inoko H (2004). "Molecular analysis of HLA allele frequencies and haplotypes in Baloch of Iran compared with related populations of Pakistan". Tissue Antigens 64 (5): 581–587. doi:10.1111/j.1399-0039.2004.00302.x. PMID 15496201.

^ Shankarkumar U, Prasanavar D, Ghosh K, and Mohanty D (2003). "HLA A*02 allele frequencies and B haplotype associations in Western Indians". Hum Immunol. 64 (5): 562–566. doi:10.1016/S0198-8859(03)00032-6. PMID 12691707.

^ V. Apanius, D. Penn, P.R. Slev, L.R. Ruff, and W.K. Potts (1997). "The nature of selection on the major histocompatibility complex". Critical Reviews in Immunology 17 (2): 179–224. PMID 9094452..

^ Wedekind C, Seebeck T, Bettens F, and Paepke AJ (1995). "MHC-dependent mate preferences in humans". Proc Biol Sci. 260 (1359): 245–249. doi:10.1098/rspb.1995.0087. PMID 7630893.

^ Oshima M, Deitiker P, Ashizawa T, Atassi M (2002). "Vaccination with a MHC class II peptide attenuates cellular and humoral responses against tAChR and suppresses clinical EAMG". Autoimmunity 35 (3): 183–90. doi:10.1080/08916930290022270. PMID 12389643.

^ Verlinsky Y, Rechitsky S, Schoolcraft W, Strom C, Kuliev A (Jun 2001). "Preimplantation diagnosis for Fanconi anemia combined with HLA matching". JAMA 285 (24): 3130–3. doi:10.1001/jama.285.24.3130. PMID 11427142. http://jama.ama-assn.org/cgi/pmidlookup?view=long&pmid=11427142.HLA and autoimmune diseases

출처: http://en.wikipedia.org/wiki/Human_leukocyte_antigen