제 1 장 의학유전학의 개요

의학 유전학이란 인간의 건강과 질병에 관련된 생물학적 변이에 관한 과학이다, 인간 개개인이 서로 다르며, 자식이 부모를 닮는다는 것, 어떤 질병들은 대를 이어 물려진다는 것이 이미 오래 전부터 알려져 온 사실이지만, 그 과학적 기초는 겨우 지난 125년간에 걸쳐서 연구되어져 왔다. 이러한 지식의 임상적 적용은 최근 35년간에 걸쳐서 이루어지고 있다.

1. 의학유전학의 과학적 기초

1.1 멘델의 공로

ㆍ멘델 이전의 세대에서는 부모의 형질이 섞여서 자손에게 전해진다고 믿었음. 이러한 생각은 키, 피부색깔과 같은 연속적 형질의 유전에는 적용가능 했지만, 백색증, 혈우병과 같은 불연속적 형질의 유전을 설명할 수 없었다.

ㆍ멘델의 제 1 법칙 : 멘델은 단일 형질(완두콩의 색깔 혹은 완두콩의 모양)의 유전에 대한 그의 완두콩 실험(Fig. 1.1, Fig. 1.2)에 의해, 유전은 서로 섞일 수 없는 그리고 쌍으로 된 입자성 요소(gene)에 의해 일어나며, 쌍으로 된 유전자 각각이 서로 다른 생식세포로 분리되어진다는 결론을 내림(Law of Segregation).

ㆍ멘델의 제 2 법칙 : 복수형질(완두콩의 색깔과 모양을 동시에 관찰)의 유전에 대한 실험에서 서로 다른 유전자 쌍은 생식세포로 분리되어질 때 서로 독립적으로 분리되어진다는 결론을 내림(Law of Independent Assortment)

1.2 염색체가 유전을 담당한다.

MENDEL'S GENETIC LAWS

출처: http://www.hobart.k12.in.us/jkousen/Biology/mendel.htm

Once upon a time (1860's), in an Austrian monastery, there lived a monk named Mendel, Gregor Mendel. Monks had a lot of time on there hands and Mendel spent his time crossing pea plants. As he did this over &over &over &over &over again, he noticed some patterns to the inheritance of traits from one set of pea plants to the next. By carefully analyzing his pea plant numbers (he was really good at mathematics), he discovered three laws of inheritance.

Mendel's Laws are as follows:

1. the Law of Dominance
2. the Law of Segregation
3. the Law of Independent Assortment

Now, notice in that very brief description of his work that the words "chromosomes" or "genes" are nowhere to be found.  That is because the role of these things in relation to inheritance &heredity had not been discovered yet. What makes Mendel's contributions so impressive is that he described the basic patterns of inheritance before the mechanism for inheritance (namely genes) was even discovered.

Hail to the "Father of Genetics" !

My name is ma-ma-ma-ma-ma-Mendel.

There are a few important vocabulary terms we should iron-out before diving into Mendel's Laws.

GENOTYPE = the genes present in the DNA of an organism.  We will use a pair of letters (ex: Tt or YY or ss, etc.) to represent genotypes for one particular trait.  There are always two letters in the genotype because (as a result of sexual reproduction) one code for the trait comes from mama organism &the other comes from papa organism, so every offspring gets two codes (two letters).

Now, turns out there are three possible GENOTYPES - two big letters (like "TT"), one of each ("Tt"), or two lowercase letters ("tt"). Since WE LOVE VOCABULARY, each possible combo has a term for it.

When we have two capital or two lowercase letters in the GENOTYPE (ex: TT or tt) it's called HOMOZYGOUS ("homo" means "the same").  Sometimes the term "PURE" is used instead of homozygous.

When the GENOTYPE is made up of one capital letter &one lowercase letter (ex: Tt) it's called HETEROZYGOUS ("hetero" means "other").  Just to confuse you, a heterozygous genotype can also be referred to as HYBRID. OK?

Let's Summarize:

Genotype = genes present in an organism (usually abbreviated as two letters)
TT = homozygous = pure	Tt = heterozygous = hybrid	tt = homozygous = pure

PHENOTYPE = how the trait physically shows-up in the organism.  Wanna know the simplest way to determine an organism's phenotype ?  Look at it.  Examples of phenotypes: blue eyes, brown fur, striped fruit, yellow flowers.

ALLELES = (WARNING - THIS WORD CONFUSES PEOPLE; READ SLOW) alternative forms of the same gene.  Alleles for a trait are located at corresponding positions on homologous chromosomes.
Remember just a second ago when explaining genotypes I said that "one code (letter) comes from ma &one code (letter) comes from pa"? Well "allele" is a fancy word for what I called codes.

For example, there is a gene for hair texture (whether hair is curly or straight).  One form of the hair texture gene codes for curly hair.  A different code for of the same gene makes hair straight.  So the gene for hair texture exists as two alleles --- one curly code, and one straight code.

Let's try &illustrate with a diagram.
In this picture the two "hot dog" shapes represent a pair of homologous chromosomes.  Homologous chromosomes are the same size &have the same genetic info (genes).  Each letter in the diagram stands for an allele (form of a gene).  What's important to notice is that the letters can be in different forms (capital or lowercase) --- that is what we mean by allele --- and that the letters are lined-up in the same order along each hot dog --- I mean homologous chromosome. The "a-forms" are in corresponding positions, so are the "B-forms", the "c" alleles, the "d" alleles, etc. etc. OK?
Reread that "allele" definition again &study the picture.

Getting back to our abbreviations, we could use a "C" for the curly allele, and a "c" for the straight allele.  A person's genotype with respect to hair texture has three possiblilties: CC, Cc, or cc.  So to review some vocab, homozygous means having two of the same allele in the genotype (2 big or 2 little letters --- CC or cc).  Heterozygous means one of each allele in the genotype (ex: Cc).

Now I could tell you which genotypes create curls &which do not, but then I'd be stealing some of Mr. Mendel's thunder.  More on that in a minute ........

Vocabulary Review Questions

1. Which of the following is a possible abbreviation for a genotype?

A. BC
B. Pp
C. Ty
D. fg

2. What is the best way to determine the phenotype of the feathers on a bird?

A. analyze the bird's DNA (genes)
B. look at the bird's feathers
C. look at the bird's beak
d. examine the bird's droppings

3. Which of the following pairs is not correct?

A. kk = hybrid
B. hybrid = heterozygous
C. heterozygous = Hh
D. homozygous = RR

4. The genes present in an organism represent the organism's __________.

A. genotype
B. phenotype
C. physical traits

5. Which choice represents a possible pair of alleles?

A. k &t
B. K &T
C. K &k
D. K &t

6. How many alleles for one trait are normally found in the genotype of an organism?

A. 1
B. 2
C. 3
D. 4

7. Which statement is not true?

A. genotype determines phenotype
B. phenotype determines genotype
C. a phenotype is the physical appearance of a trait in an organism
D. alleles are different forms of the same gene

<answers are here>

Ma-Ma-Ma-Ma-Mendel's First Law

The Law of Dominance
Stated "simply" it goes like so:
In a cross of parents that are pure for contrasting traits, only one form of the trait will appear in the next generation.  Offspring that are hybrid for a trait will have only the dominant trait in the phenotype.

While Mendel was crossing (reproducing) his pea plants (over &over &over again), he noticed something interesting.  When he crossed pure tall plants with pure short plants, all the new pea plants (referred to as the F1 generation) were tall.  Similarly, crossing pure yellow seeded pea plants and pure green seeded pea plants produced an F1 generation of all yellow seeded pea plants.  The same was true for other pea traits:

Parent Pea Plants	F1 Pea Plants
tall stem x short stem	all tall stems
yellow seeds x green seeds	all yellow seeds
green pea pods x yellow pea pods	all green pea pods
round seeds x wrinkled seeds	all round seeds
axial flowers x terminal flowers	all axial flowers

So, what he noticed was that when the parent plants had contrasting forms of a trait (tall vs short, green vs yellow, etc.) the phenotypes of the offspring resembled only one of the parent plants with respect to that trait.  So, he said to himself,

"Greg, there is a factor that makes pea plants tall, and another factor that makes pea plants short. Furthermore Greg ol' boy, when the factors are mixed, the tall factor seems to DOMINATE the short factor".

Now, in our modern wisdom, we use "allele" or "gene" instead of what Mendel called "factors".   There is a gene in the DNA of pea plants that controls plant height (makes them either tall or short).  One form of the gene (allele) codes for tall, and the other allele for plant height codes for short.  For abbreviations, we use the capital "T" for the dominant tall allele, and the lowercase "t" for the recessive short allele.

Let's revisit the three possible genotypes for pea plant height &add some MORE VOCABULARY.

Genotype Symbol	Genotype Vocab	Phenotype
TT	homozygous DOMINANT or pure tall	tall
Tt	heterozygous or hybrid	tall
tt	homozygous RECESSIVE or pure short	short

Note: the only way the recessive trait shows-up in the phenotype is if the geneotype has 2 lowercase letters (i.e. is homozygous recessive).
Also note: hybrids always show the dominant trait in their phenotype (that, by the way,  is Mendel's Law of Dominance in a nutshell).

The PUNNETT SQUARE (P-Square for short)

OK, now is as good of time as any to introduce you to a new friend, the Punnett Square.  This little thing helps us illustrate the crosses Mendel did, and will assist you in figuring out a multitude of genetics problems.

We will start by using a P-Square to illustrate Mendels Law of Dominance.  Recall that he "discovered" this law by crossing a pure tall pea plant &a pure short pea plant.  In symbols, that cross looks like this:

Parents (P):  TT x tt

where T = the dominant allele for tall stems
&  t = recessive allele for short stems

The P-Square for such a cross looks like this:
Inside the 4 boxes are the possible genotypes (with respect to plant height) of the offspring from these parent pea plants.  In this case, the only possible genotype is Tt (heterozygous).  In hybrids, the dominant trait (whatever the capital letter stands for) is the one that appears in the phenotype, so all the offspring from this cross will have tall stems.

To "fill in the boxes" of the Punnett Square, say to yourself "letter from the left &letter from the top".  The "t" from the left is partnered with the "T" from the top to complete each of the four squares.

A summary of this cross would be:

Parent Pea Plants (P Generation)		Offspring (F1 Generation)
Genotypes: TT x tt	Phenotypes: tall x short	Genotypes: 100% Tt	Phenotypes: 100% tall

Now, a helpful thing to recognize is this:

ANY TIME TWO PARENT ORGANISMS LOOK DIFFERENT FOR A TRAIT,
AND ALL THEIR OFFSPRING RESEMBLE ONLY ONE OF THE PARENTS,
YOU ARE DEALING WITH MEDEL'S LAW OF DOMINANCE.

All the offspring are heterozygous for the trait, one parent is homozygous dominant, and the other is homozygous recessive.

Does setting up &using the Punnett Square confuse you? Would you like to see a step-by-step "how to" about the good ol' p-square?
If you said "yes", then check this out:  "The Punnet Square (in baby steps)".

For some practice Punnett Square problems visit my very own: "P-Square Practice Page".

Don't forget to come back &learn more about Mendel!

Ma-Ma-Ma-Ma-Mendel's Second Law

The Law of Segregation
Goes like so: During the formation of gametes (eggs or sperm), the two alleles responsible for a trait separate from each other.  Alleles for a trait are then "recombined" at fertilization, producing the genotype for the traits of the offspring.

The way I figure it, Mendel probably got really bored crossing pure dominant trait pea plants with pure recessive trait pea plants (over &over &over again) &getting nothing but pea plants with the dominant trait as a result.  Except for gaining more &more evidence for his Law of Dominance, this probably grew tiresome.  So, at one point he takes the offspring of a previous cross &crosses them.  Ooooooooh ............

Recall that his original cross for the tall &short pea plants was:

	Parents	F1 Offspring
Genotype(s)	TT x tt	100% Tt
Phenotype(s)	tall x short	100% tall

So, he takes two of the "F1" generation (which are tall) &crosses them.  I would think that he is figuring that he's gonna get all tall again (since tall is dominant).  But no!  Low &behold he gets some short plants from this cross! His new batch of pea plants (the "F2" generation) is about 3/4 tall &1/4 short. So he says to himself,

"Greg ol' boy, the parent plants for this cross each have one tall factor that dominates the short factor &causes them to grow tall. To get short plants from these parents, the tall &short factors must separate, otherwise a plant with just short factors couldn't be produced. The factors must SEGREGATE themselves somewhere between the production of sex cells &fertilization."

I think it's easier to picture this law by using a p-square.  Our cross is two hybrid parents, Tt x Tt.
The punnet square would look like this:
Now, when completing a Punnet Square, we model this "Law of Segregation" every time.  When you "split" the genotype letters &put one above each column &one in front of each row, you have SEGREGATED the alleles for a specific trait. In real life this happens during a process of cell division called "MEIOSIS".  Meiosis leads to the production of gametes (sex cells), which are either eggs or sperm. Sometimes the term "GAMETOGENESIS" is used instead of meiosis.  Scientists love vocabulary (sorry).

You can see from the p-square that any time you cross two hybrids, 3 of the 4 boxes will produce an organism with the dominant trait (in this example "TT", "Tt", &"Tt"), and 1 of the 4 boxes ends up homozygous recessive, producing an organism with the recessive phenotype ("tt" in this example).

Our summary:

Parent Pea Plants (Two Members of F1 Generation)		Offspring (F2 Generation)
Genotypes: Tt x Tt	Phenotypes: tall x tall	Genotypes: 25% TT 50% Tt 25% tt	Phenotypes: 75% tall 25% short

A helpful thing to recognize:

Any time two parents have the same phenotype for a trait
but some of their offspring look different with respect to that trait,
the parents must be hybrid for that trait.

Ma-Ma-Ma-Ma-Mendel's Third Law

The Law of Independent Assortment
Alleles for different traits are distributed to sex cells (& offspring) independently of one another.

OK. So far we've been dealing with one trait at a time.  For example,  height (tall or short), seed shape (round or wrinkled), pod color (green or yellow), etc.  Mendel noticed during all his work that the height of the plant and the shape of the seeds and the color of the pods had no impact on one another.  In other words, being tall didn't automatically mean the plants had to have green pods, nor did green pods have to be filled only with wrinkled seeds, the different traits seem to be inherited INDEPENDENTLY.

Please note my emphasis on the word "different".  Nine times out of ten, in a question involving two different traits, your answer will be "independent assortment".  There is a big ugly punnet square that illustrates this law so I guess we should take a look at it.  It involves what's known as a "dihybrid cross", meaning that the parents are hybrid for two different traits.

The genotypes of our parent pea plants will be:

RrGg x RrGg

where
"R" = dominant allele for round seeds
"r" = recessive allele for wrinkled seeds
"G" = dominant allele for green pods
"g" = recessive allele for yellow pods

Notice that we are dealing with two different traits: (1) seed texture (round or wrinkled) &(2) pod color (green or yellow).  Notice also that each parent is hybrid for each trait (one dominant &one recessive allele for each trait).

We need to "split" the genotype letters &come up with the possible gametes for each parent.  Keep in mind that a gamete (sex cell) should get half as many total letters (alleles) as the parent and only one of each letter. So each gamete should have one "are" and one "gee" for a total of two letters.  There are four possible letter combinations: RG, Rg, rG, and rg. These gametes are going "outside" the p-square, above 4 columns &in front of 4 rows.  We fill things in just like before --- "letters from the left, letters from the top". When we finish each box gets four letters total (two "are's" &two "gees").

This is what it looks like:

	RG	Rg	rG	rg
RG	RRGG round	RRGg round	RrGG round	RrGg round
Rg	RRGg round	RRgg round	RrGg round	Rrgg round
rG	RrGG round	RrGg round	rrGG wrinkled	rrGr wrinkled
rg	RrGg round	Rrgg round	rrGg wrinkled	rrgg wrinkled

The results from a dihybrid cross are always the same:
9/16 boxes (offspring) show dominant phenotype for both traits (round &green),
3/16 show dominant phenotype for first trait &recessive for second (round &yellow),
3/16 show recessive phenotype for first trait &dominant form for second (wrinkled &green), &
1/16 show recessive form of both traits (wrinled &yellow).

So, as you can see from the results, a green pod can have round or wrinkled seeds, and the same is true of a yellow pod.  The different traits do not influence the inheritance of each other.  They are inherited INDEPENDENTLY.

Interesting to note is that if you consider one trait at a time, we get "the usual" 3:1 ratio of a single hybrid cross (like we did for the LAw of Segregation). For example, just compare the color trait in the offspring; 12 green &4 yellow (3:1 dominant:recessive).  Same deal with the seed texture; 12 round &4 wrinkled (3:1 ratio).  The traits are inherited INDEPENDENTLY of eachother --- Mendel's 3rd Law.

Summary:

I would like to summarize Mendel's Laws by listing the cross that illustrates each.

LAW	PARENT CROSS	OFFSPRING
DOMINANCE	TT x tt tall x short	100% Tt tall
SEGREGATION	Tt x Tt tall x tall	75% tall 25% short
INDEPENDENT ASSORTMENT	RrGg x RrGg round &green x round &green	9/16 round seeds &green pods 3/16 round seeds &yellow pods 3/16 wrinkled seeds &green pods 1/16 wrinkled seeds &yellow pods

There you have them, Mendel's huge contributions to the world of science.  A very smart cookie.  His work has stood the test of time, even as the discovery &understanding of chromosomes &genes has developed in the 140 years after he published his findings.  New discoveries have found "exceptions" to Mendel's basic laws, but none of Mendel's things have been proven to be flat-out wrong.

Hail to the "Father of Genetics" !

The name is ma-ma-ma-ma-ma-Mendel.

Review Questions

1. Which cross would best illustrate Mendel's Law of Segregation?

A. TT x tt
B. Hh x hh
C. Bb x Bb
D. rr x rr

2. In the cross Yy x Yy, what percent  of offspring would have the same phenotype as the parents?

A. 25%
B. 50%
C. 75%
D. 100%

3. In a certain plant, purple flowers are dominant to red flowers.  If the cross of two purple-flowered plants produces some some purple-flowered and some red-flowered plants, what is the genotype of the parent plants?

A. PP x Pp
B. Pp x Pp
C. pp x PP
D. pp x pp

Base questions #4-8 on the following information:

A white-flowered plant is crossed with a pink-flowered plant.  All of the F1 offspring from the cross are white.

4. Which phenotype is dominant?
5. What are the genotypes of the original parent plants?
6. What is the genotype of all the F1 offspring?
7. What would be the percentages of genotypes &phenotypes if one of the white F1 plants is crossed with a pink-flowered plant?
8. Which of Mendel's Laws is/are illustrated in this question?

9. Crossing two dihybrid organisms results in which phenotypic ratio?

A. 1:2:1
B. 9:3:3:1
C. 3:1
D. 1:1

10. The outward appearance (gene expression) of a trait in an organism is referred to as:

A. genotype
B. phenotype
C. an allele
D. independent assortment

11. In the homologous chromosomes shown in the diagram, which is a possible alleleic pair?

A. cD
B. Ee
C. AB
D. ee

12. The phenotype of a pea plant can best be determined by:

A. analyzing its genes
B. looking at it
C. crossing it with a recessive plant
D. eating it

13. Mendel formulated his Law of Segregation after he had:

A. studied F1 offspring
B. studied F2 offspring
C. produced mutations
D. produced hybrids

14. Which cross would produce phenotypic ratios that would illustrate the Law of Dominance?

A. TT x tt
B. TT x Tt
C. Tt x Tt
D. tt x tt

15. The mating of two curly-haired brown guinea pigs results in some offspring with brown curly hair, some with brown straight hair, some with white curly hair, and even some with white straight hair.  This mating illustrates which of Mendel's Laws?

A. Dominance
B. Segregation
C. Independent Assortment
D. Sex-Linkage

<Answers to Review Questions>

If you haven't already, be sure to visit the P-Square Practice Page!

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Answers Area

Vocabulary Term Review Questions - CORRECT ANSWERS ARE UNDERLINED

1. Which of the following is a possible abbreviation for a genotype?

A. BC
B. Pp - genotypes are made up of 2 of the same letter (either 2 capital, 2 lowercase, or one of each)
C. Ty
D. fg

2. What is the best way to determine the phenotype of the feathers on a bird?

A. analyze the bird's DNA (genes)
B. look at the bird's feathers - "phenotype of the feathers" means what the feathers look like, so look at 'em
C. look at the bird's beak
d. examine the bird's droppings

3. Which of the following pairs is not correct?

A. kk = hybrid - Kk would be hybrid (one capital, one lowercase of the same letter)
B. hybrid = heterozygous
C. heterozygous = Hh
D. homozygous = RR

4. The genes present in an organism represent the organism's __________.

A. genotype
B. phenotype
C. physical traits

5. Which choice represents a possible pair of alleles?

A. k &t
B. K &T
C. K &k - allele means 2 forms of the same gene. so this choice shows 2 forms of the same letter K or k
D. K &t

6. How many alleles for one trait are normally found in the genotype of an organism?

A. 1
B. 2 - one allele is inherited from each parent
C. 3
D. 4

7. Which statement is not true?

A. genotype determines phenotype - (note that the environment does play a role in influencing phenotype too)
B. phenotype determines genotype
C. a phenotype is the physical appearance of a trait in an organism
D. alleles are different forms of the same gene - (see question #5)

<back>

Review Questions - ANSWERED &EXPLAINED

1. Which cross would best illustrate Mendel's Law of Segregation?

A. TT x tt
B. Hh x hh
C. Bb x Bb - both parent show dominant trait, but some recessive offspring will be produced (each parent carries a "b")
D. rr x rr

2. In the cross Yy x Yy, what percent  of offspring would have the same phenotype as the parents?

A. 25%
B. 50%
C. 75% - in the completed p-square, 3 of 4 boxes will have at least 1 "Y", producing the dominant phenotype (same as parents)
D. 100%

3. In a certain plant, purple flowers are dominant to red flowers.  If the cross of two purple-flowered plants produces some some purple-flowered and some red-flowered plants, what is the genotype of the parent plants?

A. PP x Pp
B. Pp x Pp - for any offspring to be recessive, each parent MUST have at leat one "p"
C. pp x PP - only one parent is purple, this CAN'T be an answer
D. pp x pp - neither parent is purple, this CAN'T be an answer

Base questions #4-8 on the following information:

A white-flowered plant is crossed with a pink-flowered plant.  All of the F1 offspring from the cross are white.

4. Which phenotype is dominant? white
5. What are the genotypes of the original parent plants? WW (pure white) x ww (pink)
6. What is the genotype of all the F1 offspring? Ww (white)
7. What would be the percentages of genotypes &phenotypes if one of the white F1 plants is crossed with a pink-flowered plant?

50% heterozygous  white &50% homozygous recessive pink.

The cross for this question would be "Ww (white F1) x ww (pink)".
The alleles of the  white parent are above the columns &those of the pink parent are in front of the rows. 2 of 4 boxes (50%) are "Ww", which is heterozygous &would have the dominant trait (white).  The other 2 of 4 boxes (50%) are "ww", which is homozygous recessive &would have the recessive trait (pink).

8. Which of Mendel's Laws is/are illustrated in this question? Dominance is illustrated by the original cross (WW x ww).

9. Crossing two dihybrid organisms results in which phenotypic ratio?

A. 1:2:1 - genotype ratio of a hybrid cross, ex: Tt x Tt
B. 9:3:3:1- dihybrid means hybrid for two different traits. An example could be GgYy x GgYy.
C. 3:1 - phenotype ratio of a hybrid cross
D. 1:1

10. The outward appearance (gene expression) of a trait in an organism is referred to as:

A. genotype
B. phenotype
C. an allele
D. independent assortment

11. In the homologous chromosomes shown in the diagram, which is a possible alleleic pair?

A. cD
B. Ee- a possible allelic pair but NOT SHOWN IN THE DIAGRAM, so this CAN'T be an answer
C. AB
D. ee - an "allelic pair" is always two forms of the same letter.  In this example they are two lowercase "e's".

12. The phenotype of a pea plant can best be determined by:

A. analyzing its genes
B. looking at it
C. crossing it with a recessive plant
D. eating it

13. Mendel formulated his Law of Segregation after he had:

A. studied F1 offspring -
B. studied F2 offspring - he crossed two hybrids (F1's) and got a second generation --- the F2.
C. produced mutations - Mendel knew NOTHING about mutations so this CAN'T be an answer
D. produced hybrids

14. Which cross would produce phenotypic ratios that would illustrate the Law of Dominance?

A. TT x tt - one parent tall, the other short, all offspring would be tall
B. TT x Tt
C. Tt x Tt - illustrates Segregation
D. tt x tt

15. The mating of two curly-haired brown guinea pigs results in some offspring with brown curly hair, some with brown straight hair, some with white curly hair, and even some with white straight hair.  This mating illustrates which of Mendel's Laws?

A. Dominance
B. Segregation
C. Independent Assortment - the question involves two different traits (hair color & hair texture), this is the only law that deals with two different traits
D. Sex-Linkage - Mendel knew NOTHING about sex-linkage so this CAN'T be an answer

ㆍ1903년 Sutton 과 Boveri 는 생식세포 형성시에 염색체의 이동과 유전 요소(유전자)의 이동이 동일함을 보고하였으며, 염색체가 유전자를 갖고 있음이 발견됨. 그러나 염색체가 단백질과 핵산으로 구성되어 있으므로 어느 것이 유전을 담당하는지 알 수 없었음.

1.3 유전의 화학적 기초

ㆍ1928년 Griffith는 열로 가열한 병원성 pneumococci 추출물이 비 병원성 pneumococci를 병원성으로 전환(형질전환)시킬 수 있음을 보임.

Figure 1.1 Mendel's breeding experiment for a single trait(color)

Figure 1.2 Mendel's experiment for a single trait(shape)

Figure 1.3 Mendel's experiment for  two traits

ㆍ1944년 Avery 와 McCarty는 핵산이 형질전환을 일으키는 물질임을 증명

ㆍ1953년 Watson 과 Crick이 DNA의 구조를 밝힘(이중나선구조)

Discovery of the Function of DNA Resulted from the Work of Multiple Scientists

출처: http://www.nature.com/scitable/topicpage/discovery-of-the-function-of-dna-resulted-6494318

The chemical nature and structure of DNA were not elucidated until the middle of the twentieth century. Prior to that point, scientists had spent years speculating about which of the many types of molecules within cells contained the hereditary information. Was it protein? Was it something else — perhaps even a molecule they had yet to discover? Eventually, researchers zeroed in on DNA as the substance responsible for the transfer of traits from one generation to the next. From there, the race was on to learn more about this remarkable molecule.

Who first identified DNA?

More on the discovery of DNA

Where is the proof that DNA is the hereditary material?: The experiments of Griffith, Avery, Hershey, and Chase

Intrigued by the structure of DNA: The contribution of Maurice Wilkins

Although James Watson and Francis Crick determined the double-helical structure of DNA, DNA itself was identified nearly 90 years earlier by Swiss chemist Friedrich Miescher. While studying white blood cells, Miescher isolated a previously unknown type of molecule that was slightly acidic and contained a high percentage of phosphorus. Miescher named this molecule "nuclein," which was later changed to "nucleic acid" and eventually to "deoxyribonucleic acid," or DNA. Interestingly, Miescher did not believe that nuclein was the carrier of hereditary information, because he thought it lacked the variability necessary to account for the incredible diversity among organisms. Rather, like most scientists of his time, Miescher believed that proteins were responsible for heredity, because they existed in such a wide variety of forms.

Who linked DNA to heredity?

For multiple decades following Miescher's discovery, most scientists continued to believe that protein, not DNA, was the carrier of hereditary information. This changed in 1944, when biologist Oswald Avery performed a series of groundbreaking experiments with the bacteria that cause pneumonia. At the time, scientists knew that some types of these bacteria (called "S type") had an outer layer called a capsule, but other types (called "R type") did not. Through a series of experiments, Avery and his colleagues found that only DNA could change R type bacteria into S type. This meant that something about DNA allowed it to carry instructions from one cell to another. This was not true of any other substances within the bacteria, including protein. This result highlighted DNA as the "transforming factor," thereby making it the best candidate for the hereditary material.

Who confirmed Avery's findings?

Figure 1: A bacteriophage infects a bacterial cell by inserting its own DNA into that cell.

As is often the case with such discoveries, Avery's findings were largely unaccepted as evidence for DNA as the hereditary material until separate experiments were performed by other scientists. Thus, eight years later, Alfred Hershey and Martha Chase further confirmed that protein was not the hereditary material through their work with bacteriophages, which are viruses that infect bacteria (Figure 1). Bacteriophages are composed of only two substances: protein and DNA. By using radioactive labels that would integrate specifically into either DNA or protein, but not both, Hershey and Chase were able to show that DNA is the only material transferred directly from bacteriophages into bacteria when the bacteria are infected by these viruses. This observation was important, because Hershey and Chase knew that the end result of bacteriophage infection was the production of more viruses in multiple copies.

Figure 2: Viral DNA (in purple) hijacks the bacterial cell, forcing it to make copies of this DNA and manufacture new viruses.

But just how did the injection of viral DNA into a bacterium create new viruses? Hershey and Chase admitted that they were unsure of the answer to this question; however, they knew it didn't have anything to do with protein, but did have something to do with DNA. Thanks to additional research, scientists now know that the DNA in a virus can take over a bacterial cell, causing it to replicate only the viral DNA and to create new viruses (Figure 2). This process is a form of hijacking, wherein the viral life-form takes over the regular machinery inside another life-form (in this case, a single bacterial cell).

Under normal circumstances, a bacterial cell will reproduce by a form of cell division called binary fission. When Avery, MacLeod, McCarty, Hershey, and Chase performed their experiments, scientists knew that binary fission involved the copying of the hereditary substance and the redistribution of this substance into two new cells. So, when DNA was proven to be the material responsible for controlling the operations inside a single cell, it became easier to understand how the process of cell division and the transfer of the DNA could control the characteristics of newly born cells. Therefore, although they did not state it explicitly, Hershey and Chase had presented experiments that clearly suggested that DNA controls the production of more DNA, and that DNA itself was the substance that directed the construction and function of living things.

Only one year after Hershey and Chase performed these experiments, James Watson and Francis Crick determined the three-dimensional structure of DNA. This discovery enabled investigators to put together the story of how DNA carries hereditary information from cell to cell. Indeed, the experiments connecting heredity and the structure of DNA were happening in parallel, so the next few years would be an exciting time for the discovery of DNA function.

1.4 염색체 이상 질병

ㆍ1959년  인간염색체 이상이 처음으로 21번 염색체에서 발견 : trisomy 21

ㆍ1970년까지 20 가지의 염색체 이상 질병이 발견

ㆍ1990년 가지 600 가지 이상의 염색체 이상이 발견

1.5 미토콘드리아 질병

ㆍ미토콘드리아는 자신의 염색체를 갖고 있음

ㆍ미토콘드리아 유전은 엄마로부터 그 자손들에게 유전(모계유전)

ㆍ미토콘드리아 유전자의 돌연변이는 질병을 일으킴

ㆍ1988년 모계유전으로 유전되는 시신경장애 질병인 Leber optic neuropathy를 들 수 있다.

Mitochondrial Disease

출처: http://www.mitochondrialdiseases.org/mitochondrial_disease.php

Overview of Mitochondrial Disease

Mitochondrial disease or dysfunction is an energy production problem. Almost all cells in the body have mitochondria, which are tiny "power plants" that produce a body's essential energy.

Mitochondrial disease means the power plants in cells don't function properly. When that happens, some functions in the body don't work normally. It's as if the body has a power failure: there is a gradation of effects, like a 'brown out' or a 'black out'.

Scientifically, it is actually a category or group of diseases. That's why mitochondrial disease takes many different forms and no two people may look alike.

It can look like any number of better known diseases: Autism, Parkinson's, Alzheimer's, Lou Gehrig's disease, muscular dystrophy and, chronic fatigue. Staying with the power plant analogy, power plants provide energy to a large community with each part of the community requiring varying degrees of power; in the same way, mitochondria provide energy to various organs of the body. So, when there is a mitochondrial dysfunction, a "black out" looks like Leigh's Disease, severe and fatal, while a "brown out" might be severe, but not lethal.

What Happens To You When You Get It?

Mitochondrial disease primarily affects brain, heart and muscle in varying levels of severity.

Depending on which cells of the body are affected, symptoms may include:

Poor growth

Loss of muscle coordination, muscle weakness

Visual and/or hearing problems

Developmental delays, learning disabilities

Mental retardation

Heart, liver or kidney disease

Gastrointestinal disorders, severe constipation

Respiratory disorders

Diabetes

Increased risk of infection

Neurological problems, seizures

Thyroid dysfunction

Dementia

In school, children with mitochondrial disease often seem to work in "spurts" and then "peter out," becoming lethargic and finding it difficult to concentrate. It is essential to understand that these periods of fatigue are not due to the child "zoning out," but rather total exhaustion from deep within the cellular level of their existence.

It ranges from intermittent difficulty thinking, remembering, moving and acting, to severe handicaps. Some results may be fatigue, muscle weakness and diabetes. And all this is overlaid by good and bad days caused by significant inconsistency-like the electricity flickering in different areas of a community.

Though the impression most have of mitochondrial disease is a disorder that presents itself at birth, it can appear at any age. For some it develops over time. We're learning it's not at all rare but, due to a lack of physician and public awareness, this disease is not often diagnosed. Only in the past 10 years, with advances in genetics and molecular biology, have we a better understanding of the complexity in mitochondrial disorders. Even so, the definitive cause (or causes) of mitochondrial disease continues to evolve.

1 in 2,500-3,000 are affected by mitochondrial disease
1 in 2,500 are affected by Cystic Fibrosis
1 in 110 individuals are affected by Autism
1 in 500 are affected by Parkinson's
1 in 85 are affected by Alzheimer's
1 in 25,000 are affected by Leigh's Disease, a fatal form of mitochondrial disease
1 in 50,000 are affected by Lou Gehrig’s Disease (ALS)

What Are the Treatments?

Currently there are no highly effective mitochondrial disease treatments. Though related symptoms, such as seizures or attention problems can be managed with various medications, the mitochondrial disease itself is unchanged. Unfortunately, supplements such as CoQ10 and L-Carnitine have little to no effect on most patients.

In 2009, FDA approval occurred for an EID (Emergency Intervention Drug) to treat a mitochondrial disease with the new drug from Edison Pharmaceuticals, EPI-743. This represents the first steps toward viable treatments and hopefully, the beginning of many more near-term advancements in mitochondrial medicine research.

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How Are Mitochondrial Diseases Diagnosed?

There is no single test to diagnose mitochondrial disease in most patients. Today, OXPHOS (oxidative phosphorylation) enzymology by itself is no longer sufficient for a diagnosis. OXPHOS is the process by which the mitochondria turn the food we eat into energy that can be used by key organs; in the same way that crude oil can't go directly into a car to make the engine run, it first needs to be refined and turned into gasoline. The mitochondria represent the most complicated enzyme system in the body, requiring over 1,000 genes to function properly. As you might guess, with so many genes, patients can present in hundreds of ways.

Diagnosis of mitochondrial disease can be made through a combination of clinical observations, laboratory evaluation, brain imaging, and muscle biopsies. And an experienced integrated approach is necessary - not just one test. Referral to a specialist in mitochondrial medicine is often needed for diagnosis. Rarely is genetic testing sufficient for the diagnosis of mitochondrial disease. Even with the advent of new gene sequencing techniques like Next Generation sequencing, many of the identified changes in genes require the information obtained from a muscle biopsy for interpretation.

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What Is Needed for Diagnosis?

In order to apply diagnostic criteria patients need testing that specifically assesses the different mechanisms causing the abnormalities (the how and the why) associated with OXPHOS defects. This understanding has evolved significantly in the past five years. And because of the complexity of the disease, continued thinking, assessing and investigating are terribly important to diagnosis accuracy. Due to the rapid changes in our understanding of mitochondrial diseases and the tools available for diagnosis, physicians need to reassess the probability of a diagnosis of mitochondrial disease as they see the patients over time. The diagnosis may change.

Most importantly, when a diagnosis of mitochondrial disease or disorder is considered, patients need to be evaluated carefully for diseases other than mitochondrial disease. For example, the muscle biopsy can be used to look at other types of muscle diseases. When a mitochondrial disease evaluation is undertaken, the physician should approach the patient comprehensively with assessments for mitochondrial diseases and other categories of disease.

It is critical for patients and their families not to oversimplify the diagnosis. In most cases, calling a patient simply a "Complex I disease" or a "Complex I and Complex III disease" is an oversimplification. By carefully understanding the complexities of patients with mitochondrial disease or disorders, the probability of an accurate diagnosis can be increased and better clinical trials can be constructed.

Download Clinical Scoring for Diagnostic Assessment.

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What Are the Tests for Mitochondrial Disease?

There are three Categories of Diagnostic Criteria: Clinical, Biochemical and Genetic. Think of it as a very long restaurant menu but, instead of selecting one from column A and one from column B, physicians involve multiple tests from these three broader categories.

CSF: cerebrospinal fluid(뇌척수액)

OXPHOSEnzymology: oxidative phosphorylation enzymology(산화적 인산화 효소학)

CoQ10: coenzyme Q(호기성 세포호흡에 관여하는 전자전달계 구성 성분)

Once these tests have been performed, experienced physicians diagnose according to specific criteria categorization:
Unlikely: Criteria-- 1-7 tests are normal
Possible: Criteria-- a single test is abnormal and the other tests are normal or equivocal
Probable: Criteria--two tests are abnormal
Highly Probable: greater than two tests are abnormal

1.6 단일 유전자 이상 질환

ㆍ1902년 Garrod가 alkaptonuria 라고하는 질병이 유전된다는 것과 멘델 유전의 열성유전을 함을 제한하였다.

* Alkaptonuria

출처: http://www.medicinenet.com/alkaptonuria/article.htm#what_is_alkaptonuria

What is alkaptonuria?

Alkaptonuria is an inherited condition that causes urine to turn black when exposed to air. Ochronosis, a buildup of dark pigment in connective tissues such as cartilage and skin, is also characteristic of the disorder. This blue-black pigmentation usually appears after age 30. People with alkaptonuria typically develop arthritis, particularly in the spine and large joints, beginning in early adulthood. Other features of this condition can include heart problems, kidney stones, and prostate stones.

Alkaptonuria (cont.)

How common is alkaptonuria?

This condition is rare, affecting 1 in 250,000 to 1 million people worldwide. Alkaptonuria is more common in certain areas of Slovakia (where it has an incidence of about 1 in 19,000 people) and in the Dominican Republic.

What genes are related to alkaptonuria?

Mutations in the HGD gene cause alkaptonuria.

The HGD gene provides instructions for making an enzyme called homogentisate oxidase. This enzyme helps break down the amino acids phenylalanine and tyrosine, which are important building blocks of proteins. Mutations in the HGD gene impair the enzyme's role in this process. As a result, a substance called homogentisic acid, which is produced as phenylalanine and tyrosine are broken down, accumulates in the body. Excess homogentisic acid and related compounds are deposited in connective tissues, which causes cartilage and skin to darken. Over time, a buildup of this substance in the joints leads to arthritis. Homogentisic acid is also excreted in urine, making the urine turn dark when exposed to air.

How do people inherit alkaptonuria?

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

* more

출처: http://health.nytimes.com/health/guides/disease/alkaptonuria/overview.html

Exams and Tests

A urine test (urinalysis) is done to test for alkaptonuria. If ferric chloride is added to the urine, it will turn the urine a black color in patients with this condition.

Treatment

Some patients benefit from high-dose vitamin C. This has been shown to decrease the build-up of brown pigment in the cartilage and may slow the development of arthritis.

Outlook (Prognosis)

The outcome is expected to be good.

Possible Complications

People with this condition also can get arthritis in adulthood. The build-up of homogentisic acid in the cartilage causes arthritis in about 50% of older adults with alkaptonuria.

Homogentisic acid also can build up on the heart valves, especially the mitral valve. This can sometimes lead to the need for valve replacement.

Coronary artery disease may develop earlier in people with alkaptonuria.

Kidney stones and prostate stones may be more common in people with alkaptonuria.

ㆍ그 이후 약 6600개의 인간 단일 유전자 이상이 알려졌다

ㆍ1956년 Ingram은 낫세포빈혈증이 헤모글로빈 단백질의 아미노산 서열에 변이가 생긴 것임을 발견함.

Sickle Cell Disease
(Sickle Cell Anemia)

출처: http://www.medicinenet.com/sickle_cell/article.htm

Medical Author:

William C. Shiel Jr., MD, FACP, FACR

What is sickle cell anemia?

How is sickle cell anemia inherited?

What conditions promote the sickling (distortion) of the red blood cells in sickle cell anemia?

How is sickle cell anemia diagnosed?

What are the symptoms and treatments of sickle cell anemia?

What is the outlook (prognosis) for patients with sickle cell anemia?

Sickle Cell Anemia At A Glance

What is sickle cell anemia?

Sickle cell anemia (sickle cell disease) is a disorder of the blood caused by an inherited abnormal hemoglobin (an oxygen-carrying protein within the red blood cells). The abnormal hemoglobin causes distorted (sickled) red blood cells. The sickled red blood cells are fragile and prone to rupture. When the number of red blood cells decreases from rupture (hemolysis), anemia is the result. This condition is referred to as sickle cell anemia. The irregular sickled cells can also block blood vessels causing tissue and organ damage and pain.

Sickle cell anemia is one of the most common inherited blood anemias. The disease primarily affects Africans and African Americans. It is estimated that in the United States, some 50,000 African Americans are afflicted with the most severe form of sickle cell anemia. Overall, current estimates are that one in 1,875 U.S. African American is affected with sickle cell anemia.

How is sickle cell anemia inherited?

Sickle cell anemia is inherited as an autosomal (meaning that the gene is not linked to a sex chromosome) recessive condition whereas sickle cell trait is inherited as an autosomal dominant trait. This means that the gene can be passed on from a parent carrying it to male and female children. In order for sickle cell anemia to occur, a sickle cell gene must be inherited from both the mother and the father, so that the child has two sickle cell genes.

The inheritance of just one sickle gene is called sickle cell trait or the "carrier" state. Sickle cell trait does not cause sickle cell anemia. Persons with sickle cell trait usually do not have many symptoms of disease and have normal hospitalization rates and life expectancies. Sickle cell trait is present in some two million blacks in the United States (8% of the U.S. black population at birth). When two carriers of sickle cell trait mate, their offspring have a one in four chance of having sickle cell anemia. (In some parts of Africa, one in five persons is a carrier for sickle cell trait.)

What conditions promote the sickling (distortion) of the red blood cells in sickle cell anemia?

Sickling of the red blood cells in patients with sickle cell anemia results in cells of abnormal shape and flexibility. The sickling is promoted by conditions which are associated with low oxygen levels, increased acidity, or low volume (dehydration) of the blood. These conditions can occur as a result of injury to the body's tissues, dehydrating states, or anesthesia.

Even certain organs are predisposed to lower oxygen levels or acidity, such as when blood moves slowly through the spleen, liver, or kidney. Also, organs with particularly high metabolism rates (such as the brain, muscles, and the placenta in a pregnant woman with sickle cell anemia) promote sickling by extracting more oxygen from the blood. These conditions make these organs susceptible to injury from sickle cell anemia.

How is sickle cell anemia diagnosed?

Sickle cell anemia is suggested when the abnormal sickle-shaped cells in the blood are identified under a microscope. Testing is typically performed on a smear of blood using a special low-oxygen preparation. This is referred to as a sickle prep. Other prep tests can also be used to detect the abnormal hemoglobin S, including solubility tests performed on tubes of blood solutions. The disease can be confirmed by specifically quantifying the types of hemoglobin present using a hemoglobin electrophoresis test.

Prenatal diagnosis (before birth) of sickle cell anemia is possible using amniocentesis or chorionic villus sampling. The sample obtained is then tested for DNA analysis of the fetal cells.

The hemoglobin electrophoresis test precisely identifies the hemoglobins in the blood by separating them. The separation of the different hemoglobins is possible because of the unique electrical charges they each have on their protein surfaces, causing them each to move characteristically in an electrical field as tested in the laboratory

What are the symptoms and treatments of sickle cell anemia?

Virtually all of the major symptoms of sickle cell anemia are the direct result of the abnormally shaped, sickled red blood cells blocking the flow of blood that circulates through the tissues of the body. The tissues with impaired circulation suffer damage from lack of oxygen. Damage to tissues and organs of the body can cause severe disability in patients with sickle cell anemia. The patients endure episodes of intermittent "crises" of variable frequency and severity, depending on the degree of organ involvement.

The major features of sickle cell anemia include:

Fatigue and Anemia

Pain Crises

Dactylitis (swelling and inflammation of the hands and/or feet) and Arthritis

Bacterial Infections

Splenic Sequestration (sudden pooling of blood in the spleen) and Liver Congestion

Lung and Heart Injury

Leg Ulcers

Aseptic Necrosis and Bone Infarcts (death of portions of bone)

Eye Damage

Other Features

Some features of sickle cell anemia, such as fatigue, anemia, pain crises, and bone infarcts can occur at any age. Many features typically occur in certain age groups.

Sickle cell anemia usually first presents symptoms in the first year of life. Infants and younger children can suffer with fever, abdominal pain, pneumococcal bacterial infections, painful swellings of the hands and feet (dactylitis), and splenic sequestration. Adolescents and young adults more commonly develop leg ulcers, aseptic necrosis, and eye damage. Symptoms in adult typically are intermittent pain episodes due to injury of bone, muscle, or internal organs.

Affected infants do not develop symptoms in the first few months of life because the hemoglobin produced by the developing fetus (fetal hemoglobin) protects the red blood cells from sickling. This fetal hemoglobin is absent in the red blood cells that are produced after birth so that by 5 months of age, the sickling of the red blood cells is prominent and symptoms begin.

The treatment of sickle cell anemia is designed according to which of the individual features of the illness are present. In general treatment is directed at the management and prevention of the acute manifestations as well as therapies directed toward blocking the red blood cells from stacking together. There is no single remedy to reverse the anemia. It is, therefore, important that family members have an optimal understanding of the illness and that communication with the doctors and medical personnel be maintained.

Fatigue and Anemia

Fatigue is a common symptom in persons with sickle cell anemia. Sickle cell anemia causes a chronic form of anemia which can lead to fatigue. The sickled red blood cells are prone to breakage (rupture) which causes a much shorter life span of these cells (the normal life span of a red blood cell is 120 days). These sickled red blood cells are easily detected with a microscope examination of a smear of blood on a glass slide.

Typically, the site of red blood cell production (bone marrow) works overtime to produce these cells rapidly, attempting to compensate for their destruction in the circulation. Occasionally, the bone marrow suddenly stops producing the red blood cells which causes a very severe form of anemia (aplastic crises). Aplastic crises can be promoted by infections that otherwise would seem less significant, including viruses of the stomach and bowels and the flu (influenza).

The anemia of sickle cell anemia tends to stabilize without specific treatments. The degree of anemia is defined by measurement of the blood hemoglobin level. Hemoglobin is the protein molecule in red blood cells which carries oxygen from the lungs to the body's tissues and returns carbon dioxide from the tissues to the lungs. Blood hemoglobin levels in persons with sickle cell anemia are generally between 6 to 8 gms/dl (normal levels are above 11 gms/dl). Occasionally, there can be a severe drop in hemoglobin requiring a blood transfusion to correct the anemia (such as in patients suffering splenic sequestration). Blood transfusion is usually reserved for those patients with other complications, including pneumonia, lung infarction, stroke, severe leg ulceration, or late pregnancy. (Among the risks of blood transfusion are hepatitis, infection, immune reaction, and injury to body tissues from iron overload.) Transfusions are also given to patients to prepare them for surgical procedures. Folic acid is given as a supplement.

Pain Crises

Pain crises in persons with sickle cell anemia are intermittent painful episodes that are the result of inadequate blood supply to body tissues. The impaired circulation is caused by the blockage of various blood vessels from the sickling of red blood cells. The sickled red blood cells slow or completely impede the normal flow of blood through the tissues. This leads to excruciating pain requiring hospitalization and narcotic medication for relief. The pain typically is throbbing and can change its location from one body area to another. Bone is frequently affected. Pain in the abdomen with tenderness is common and can mimic appendicitis. Fever frequently is associated with the pain crises.

A pain crisis can be promoted by preceding dehydration, infection, injury, cold exposure, emotional stress, or strenuous exercise. As a prevention measure, persons with sickle cell anemia should avoid extremes of heat and cold.

Pain crises require medications for pain and increased fluid intake. Dehydration must be prevented to avoid further injury to the tissues and intravenous fluids can be necessary. Along with the fluids clotrimazole and magnesium are often given. Other modalities, such as biofeedback, self-hypnosis, and/or electrical nerve stimulation may be helpful.

Hydroxyurea is a medication that is currently being used in adults and children with severe pain from sickle cell anemia. It is also considered for those with recurrent strokes and frequent transfusions. This drug acts by increasing the amount of fetal hemoglobin in the blood (this form of hemoglobin is resistant to sickling of the red blood cells). The response to hydroxyurea is variable and unpredictable from patient to patient. Hydroxyurea can be toxic to the bone marrow.

Dactylitis and Arthritis

Swelling and inflammation of the hands and/or feet is often an early sign of sickle cell anemia. The swelling involves entire fingers and/or toes and is called dactylitis. Dactylitis is caused by injury to the bones of the affected digits by repeated episodes of inadequate blood circulation. Dactylitis generally occurs in children with sickle cell anemia from age 6 months to 8 years.

Joint inflammation (arthritis) with pain, swelling, tenderness, and limited range of motion can accompany the dactylitis. Sometimes, not only the joints of the hands or feet are affected, but also a knee or an elbow.

The inflammation from dactylitis and arthritis can be reduced by anti-inflammation medications, such as ibuprofen and aspirin.

Bacterial Infection

Lung infection (pneumonia) is extremely common in children with sickle cell anemia and is also the most common reason for hospitalization. Pneumonia can be slow to respond to antibiotics. The type of bacteria that is frequently the cause of pneumonia is called pneumococcus bacteria. (This is, in part, due to the increased susceptibility to this particular bacteria when the spleen is poorly functioning.) Vaccination against pneumococcal infection is generally recommended.

Children with sickle cell anemia are also at risk for infection of the brain and spinal fluid (meningitis). Bacteria that are frequent causes of this infection include the Pneumococcus and Haemophilus bacteria.

Furthermore, children with sickle cell anemia are at risk for an unusual form of bone infection (osteomyelitis). The infection is typically from a bacteria called Salmonella.

Bacterial infections can be serious and even overwhelming for patients with sickle cell anemia. Early detection and antibiotic treatment are the keys to minimizing complications. Any child with known sickle cell anemia must be evaluated by medical professionals when fever or other signs of infection (such as unexplained pain or cough) appear.

Splenic Sequestration and Liver Congestion

It has been demonstrated that the liver, and especially the spleen, are organs that are very active in removing sickled red blood cells from the circulation of persons with sickle cell anemia. This process can accelerate suddenly. Sudden pooling of blood in the spleen is referred to as splenic sequestration.

Splenic sequestration can cause very severe anemia and even result in death.

The spleen is commonly enlarged (splenomegaly) in younger children with sickle cell anemia. As the spleen is repeatedly injured by damage from impaired blood supply, it gradually shrinks with scarring. Impairment of the normal function of the spleen increases the tendency to become infected with bacteria.

Sudden pooling of blood in the spleen (splenic sequestration) can result in a very severe anemia and death. These patients can develop shock and lose consciousness. Transfusion of blood and fluids can be critical if this occurs.

Liver enlargement (hepatomegaly) occurs as it becomes congested with red blood cells as well. The liver is often firm and can become tender. Impaired liver function can result in yellowing of the eyes (jaundice). The gallbladder, which drains bile from the liver, can fill with gallstones. Inflammation of the gallbladder (cholecystitis) can cause nausea and vomiting and require its removal.

Lung and Heart Injury

Aside from lung infection (pneumonia), the lungs of children with sickle cell anemia can also be injured by inadequate circulation of blood which causes areas of tissue death. This lung damage can be difficult to distinguish from pneumonia. These localized areas of lung tissue damage are referred to as pulmonary infarcts. Pulmonary infarcts often require a special x-ray test using a dye injected into the affected areas (angiogram) for diagnosis. Repeated pulmonary infarcts can lead to scarring of the lungs of children with sickle cell anemia by the time they reach adolescence.

The heart is frequently enlarged in children with sickle cell anemia. Rapid heart rates and murmurs are common. The heart muscle can also be injured by infarcts and iron depositing in the muscle as it leaks from the ruptured red blood cells.

Injuries to the lungs or heart are treated according to the specific type of damage and the degree of impairment of organ function. Supplementary oxygen can be required. Infections of the lungs require aggressive antibiotics. Transfusions can sometimes help prevent further damage to the lung tissue. Heart failure can require chronic heart medications to assist the heart in pumping blood to the body.

Leg Ulcers

The legs of patients with sickle cell anemia are susceptible to skin breakdown and ulceration. This seems to be a result of the stagnant blood flow caused by the sickled red blood cells. Injury to the skin of the legs or ankles can promote skin damage and ulceration.

Leg ulcers most commonly occur in adults and usually form over the ankles and sides of the lower legs. The ulcers can become severe, even encircling the leg, and are prone to infection.

Leg ulcers can become chronic and resistant to many treatments. Oral antibiotics and topical creams are often used. Elevation of the leg, careful dressing changes, and other topical therapies can be helpful. Some ulcers can be so resistant that skin grafting is recommended, though this is not without the possibility of poor healing.

Aseptic Necrosis and Bone Infarcts

Inadequate circulation of the blood, which is characteristic of sickle cell anemia, also causes areas of death of bone tissue (bone infarction). Aseptic necrosis, or localized bone death, is a result of inadequate oxygen supply to the bone. Aseptic necrosis is also referred to as osteonecrosis.

While virtually any bone can be affected, the most common are the bones of the thighs, legs, and arms. The result can permanently damage or deform the hips, shoulders, or knees. Pain, tenderness, and disability frequently are signs of aseptic necrosis. Painful bone infarcts can be relieved by rest and pain medications.

Aseptic necrosis can permanently damage large joints (such as the hips or shoulders). Local pain can be relieved and worsening of the condition can be prevented by avoiding weight bearing. With more severe damage, total joint replacement may be needed to restore function.

Eye Damage

The critical area of the eye that normally senses light is called the retina. The retina is in the back of the eye and is nourished by many tiny blood vessels. Impairment of the circulation from the sickling of red blood cells results in damage to the retina (retinopathy). The result can be partial or complete blindness.

Bleeding can also occur within the eye (retinal hemorrhage) and retinal detachment can result. Retinal detachment can lead to blindness.

Once blindness occurs, it is usually permanent. Preventative measures, such as laser treatments, can be used if bleeding into the eye and retinal detachment are detected early.

Other Features

Additional features of sickle cell anemia include weakening of bones from osteoporosis, kidney damage and infection, and nervous system damage. Osteoporosis can lead to severe pain in the back and deformity from collapse of the bony building blocks (vertebrae) of the spine. Kidney damage can lead to poor kidney function with a resulting imbalance of blood sodium and acidity as well as bleeding into the urine. Kidney infection can cause pelvic pain and require hospitalization with antibiotic treatment. Injury to the nervous system can result from meningitis or sickle cell anemia itself. Poor blood circulation in the brain can cause stroke, convulsions, and coma.

Damage to the brain from stroke can cause permanent loss of function to areas of the body. Transfusion of blood and fluids intravenously can be critical. Medications to reduce the chance of seizures are sometimes added. If stroke results in long-term impairment of function, physical therapy, speech therapy, and occupational therapy can be helpful.

Priapism, an abnormally persistent erection of the penis in the absence of sexual desire, can occur in persons with sickle cell anemia. Priapism can lead to impotence.

What is the outlook (prognosis) for patients with sickle cell anemia?

The life expectancy of persons with sickle cell anemia is reduced. Some patients, however, can remain without symptoms for years, while others do not survive infancy or early childhood. Nevertheless, with optimal management patients can now survive beyond the fourth decade.

Most patients suffer intermittent pain crises, fatigue, bacterial infections, and progressive tissue and organ damage. Impaired growth and development is the end result of the physical and emotional trauma that is endured by children with sickle cell anemia.

Causes of death include bacterial infection (the most common cause), stroke or bleeding into the brain, and kidney, heart, or liver failure. The risk of bacterial infections does diminish after three years of age. Nevertheless, bacterial infections are the most common cause of death at any age. Therefore, any signs of infection in a person with sickle cell anemia must be reviewed with a doctor to prevent damage and save lives.

Interestingly, the sickle cell gene somewhat protects against malaria infection. This makes those with sickle cell trait (gene carriers) at least partially resistant to malaria. Furthermore, the geographic distribution of the sickle cell gene is similar to that of malaria infection. Sickle cell anemia is a lethal condition that threatens life. But there may be a selective advantage to being a sickle cell carrier (trait) if the person resides in an area of the world where malaria is very common. The advantage a person with sickle cell trait has over a non-carrier of the gene may explain why sickle cell anemia did not disappear from the world even though it is lethal.

The sickle cell gene is not a "black gene." It just happens to disproportionately occur in the black population. When a black person who carries a sickle cell gene has children with a non-black person, the children may inherit the sickle cell gene regardless of their color. There are also non-black persons who carry the sickle cell gene.

Recent research is examining further ways to promote the development of the fetal hemoglobin that delays the development of sickle cell in the newborn. Bone marrow transplantation is being used for patients with severe sickle cell anemia who have a genetically identical sibling that can offer the transplant marrow. Future treatments may involve genetic engineering where cures might be achieved.

Finally, genetic counseling can be helpful for parents and families to prevent sickle cell anemia. Sickle cell anemia is an inherited illness. Both parents must be carriers of the sickle cell gene for a child to be affected with sickle cell anemia. If each parent is a carrier, any child has a one chance in two (50%) of also being a carrier and a one in four (25%) chance of inheriting both genes from the parents and being affected with sickle cell anemia.

Sickle Cell Anemia At A Glance

Sickle cell anemia is an inherited disorder of the hemoglobin in blood.

Sickle cell anemia requires the inheritance of two sickle cell genes.

Sickle cell trait, which is the inheritance of one sickle gene, almost never causes problems.

Virtually all of the major symptoms of sickle cell anemia are the direct result of the abnormally shaped sickled red blood cells blocking the flow of blood.

The current treatment of sickle cell anemia is directed primarily toward managing the individual features of the illness as they occur.

Reference:
Bunn, HF. Pathogenesis and treatment of sickle cell disease. N Engl J Med 1997; 337:762.
Harrison's Principles of Internal Medicine, McGraw-Hill, edited by Eugene Braunwald, et. al., 2001.

ㆍ지금까지 450개 종류 이상의 헤모글로빈 변이가 알려짐

ㆍ400 가지 이상의 선천성 대사장애가 알려져 있으나, 단일 유전자 이상 중 90 % 정도는 그 단백질이 무엇인지 조차 모르고 있다.

ㆍ이러한 단일 유전자 이상은 인간의 대사과정을 이해하는데 도움이 됨.

ㆍ유전자를 염색체와 연결시키는 연구가 진행되었고, 1911년에 Wilson은 색맹 유전인자가 X 염색체에 있음을 밝혔다.

ㆍ TK(thymidine kinase) 유전자가 17번 상염색체의 유전자로서 처음 밝혀짐.

Biochemistry(출처; http://en.wikipedia.org/wiki/Thymidine_kinase)

Mammals have two isoenzymes, that are chemically very different, TK1 and TK2. The former was first found in fetal tissue, the second was found to be more abundant in adult tissue, and initially they were termed fetal and adult thymidine kinase. Soon it was shown that TK1 is present in the cytoplasm only in anticipation of cell division (cell cycle-dependent),[10][11] whereas TK2 is located in mitochondria and is cell cycle-independent.[12][13] The genes of the two types were localized in the mid-1970s.[14][15] The gene for TK1 was cloned and sequenced.[16] The corresponding protein has a molecular weight of about 25 kD. Normally, it occurs in tissue as a dimer. It can be activated by ATP. After activation, it has been converted to a tetramer. The recombinant TK1 cannot be activated and converted to a tetramer in this way, showing that the enzyme occurring in cells has been modified after synthesis.[17][18][19] TK1 is synthesized by the cell during the S phase of cell division. After cell division is completed, TK1 is degraded intracelluarly, so that it does not pass to body fluids after normal cell division.[20] There is a feed-back regulation of the action of thymidine kinase in the cell: thymidine triphosphate (TTP), the product of the further phosphorylation of thymidine, acts as an inhibitor to thymidine kinase.[18][21][22][23] This serves to maintain a balanced amount of TTP available for nucleic acid synthesis, not oversaturating the system. 5'-Aminothymidine, a non-toxic analogue of thymidine, interferes with this regulatory mechanism and thereby increases the cytotoxicity of thymidine analogues used as antineoplastic drugs.[24][25][26][27][28][29][30]

Genes for virus specific thymidine kinases have been identified in Herpes simplex virus, Varicella zoster virus and Epstein-Barr virus.[31][32][33][34][35][36][37]
+ ATP --->  + ADP

Deoxythymidine reacts with ATP to give deoxythymidine monophosphate and ADP.

+ ATP ---> + ADP

ㆍ1987년 인간 염색체의 연관지도가 완성되고, 1993년 인간염색체의 물리적 지도가 완성.

Linkage map (출처:http://www.biology-online.org/dictionary/Linkage_map)

Definition

noun

A genetic map showing the relative positions of genetic markers along a chromosome that is determined by the recombination frequency during crossover of homologous chromosomes.

Supplement

Genetic linkage map shows the relative positions of genetic markers on a chromosome. The positions of genetic markers are determined based on how often the loci are inherited together rather than on the specific physical distance between them. It means that the more often the two genetic markers are inherited together the farther apart they are. In contrast, the lower frequency of being inherited together the smaller the physical distance is between them.

Physical map(출처: http://ghr.nlm.nih.gov/glossary=physicalmap)

Definition(s)

A physical map of a chromosome or a genome that shows the physical locations of genes and other DNA sequences of interest. Physical maps are used to help scientists identify and isolate genes by positional cloning.

Definition from: Talking Glossary of Genetic Terms from the National Human Genome Research Institute

A map of the locations of identifiable landmarks on DNA (e.g., restriction-enzyme cutting sites, genes), regardless of inheritance. Distance is measured in base pairs. For the human genome, the lowest-resolution physical map is the banding patterns on the 24 different chromosomes; the highest-resolution map is the complete nucleotide sequence of the chromosomes.

Definition from: Human Genome Project Information at the U.S. Department of Energy

See also Understanding Medical Terminology.

ㆍ1977년 chorionic somatomammotropin(융모몸젖샘발육호르몬) 유전자가 처음 cloning 됨(17번 염색체, placental lactogen이라고도 함)

What is human placental lactogen (hPL)? (출처: http://www.sharecare.com/question/human-placental-lactogen-hpl)

Dr. Mehmet Oz answered:

In a pregnant woman, the placenta produces a hormone called human placental lactogen (hPL). It's almost identical in structure to growth hormone that is present in all women, but in pregnant women, hPL can reach a thousand times the equivalent normal concentration. The job of hPL is to inhibit mom's insulin from getting glucose into her cells, thereby increasing mom's bloodstream glucose levels and making more available to her baby.

When hPL blocks insulin's ability to transport glucose into your cells, it allows your baby to get the glucose he needs to grow. This hormonal dance - delicate and subtle as it is - ultimately influences whether your baby will achieve a target weight during pregnancy or not. And when this dance gets a little bit out of sync - oftentimes through absolutely no fault of the mom - that's when we start to see issues that can influence both the development of your baby as he grows inside of you and your baby's future health after birth.

ㆍ1994년 질병관련 돌연변이 유전자가 350개 정도 알려짐

ㆍ2001년 인간 genome project 완성

Major Events in the
U.S. Human Genome Project
and Related Projects(출처: http://www.ornl.gov/sci/techresources/Human_Genome/project/timeline.shtml)\

2006

Human Chromosome 1 Completed, May 2006.

Human Chromosome 3 Completed, April 2006.

Human Chromosome 17 Completed, April 2006.

Human Chromosome 11 Completed, March 2006.

Human Chromosome 12 Completed, March 2006.

Human Chromosome 15 Completed, March 2006.

Human Chromosome 8 Completed, January 2006.

2005

National Geographic magazine and IBM launch the Genographic Project, a multiyear research initiative using cutting-edge genetic and computational technologies to analyze historical patterns in DNA from participants around the world to better understand our human genetic roots.

Human Chromosome 4 Completed, April 2005.

Human Chromosome 2 Completed, April 2005.

Human Chromosome X Completed, March 2005.

2004

Human Chromosome 16 Completed, December 2004.

Landmark Paper: Finishing the euchromatic sequence of the human genome, Nature, Oct. 21, 2004

Human Gene Count Estimates Changed to 20,000 to 25,000, October 2004.

Human Chromosome 5 Completed, September 2004.

Landmark Paper: Human genome: Quality assessment of the human genome sequence. Nature 429, 365-368 (27 May 2004)

Human Chromosome 9 Completed, May 2004.

Human Chromosome 10 Completed, May 2004.

Human Chromosome 18 Completed, March 2004.

Human Chromosome 19 Completed, March 2004.

Human Chromosome 13 Completed, March 2004.

2003

Human Chromosome 6 Completed, October 2003.

NIH National Human Genome Research Institute (NHGRI) launched a public research consortium named ENCODE, the Encyclopedia Of DNA Elements, in September 2003, to carry out a project to identify all functional elements in the human genome sequence.

Human Chromosome 7 Completed, July 2003.

Human Chromosome Y Completed, June 2003.

Human Genome Project Declared Finished, April 2003.
[Corresponding Nature and Science]

Human Chromosome 14 Finished - Chromosome 14 is the fourth chromosome to be completely sequenced, January 2003.

2002

International HapMap Project begins.

Mouse Genome Sequencing Consortium publishes its draft sequence of mouse genome in the December 5, 2002, issue of Nature.

International consortium led by the DOE Joint Genome Institute publishes draft sequence of Fugu rubripes.

2001

Human Chromosome 20 Finished - Chromosome 20 is the third chromosome completely sequenced to the high quality specified by the Human Genome Project.

Publication of Initial Working Draft Sequence February 12, 2001
Special issues of Science (Feb. 16, 2001) and Nature (Feb. 15, 2001) contain the working draft of the human genome sequence. Nature papers include initial analysis of the descriptions of the sequence generated by the publicly sponsored Human Genome Project, while Science publications focus on the draft sequence reported by the private company, Celera Genomics. A press conference was held at 10 a.m., Monday, February 12, 2001, to discuss the landmark publications. Links for more information are:
Science
Nature
Human Genome Project and the Private Sector: A Working Partnership
Webcast of HGP Press Conference (Mon. Feb. 12, 2001)
Press releases on First Analysis of Genome Sequence

Pieter de Jong's team (now at the Oakland Children's Hospital, Oakland, CA) was a major provider of the BAC libraries used in the sequencing of the human and several other genomes.

2000

HGP leaders and President Clinton announce the completion of a "working draft" DNA sequence of the human genome.

Press briefing and remarks

An Interview with Ari Patrinos, Director U.S. DOE Human Genome Program

Part One: Reaction to President Clinton's Announcement of the Completion of a Draft Sequence of the Human Genome

Part Two: Origins of the Human Genome Project, NIH Collaboration, and the Private Sector Role

Part Three: Application of Genome Discoveries, Next Steps in the Human Genome Project, and Ethical Considerations

Craig Venter (head of Celera Genomics), Ari Patrinos (director of DOE Human
Genome Program and Biological and Environmental Research Program), and Francis Collins (director, NIH National Human Genome Research Institute).

International research consortium publishes chromosome 21 genome, the smallest human chromosome and the second to be completely sequenced.

DOE researchers announce completion of chromosomes 5, 16, and 19 draft sequence.

Elbert Branscomb, Director, Joint Genome Institute

Trevor Hawkins, Director of Sequencing, Joint Genome Institute

International collaborators publish genome of fruit fly Drosophila melanogaster.

President Clinton signs executive order prohibiting federal departments and agencies from using genetic information in hiring or promoting workers. More.

1999

First Human Chromosome Completely Sequenced! On December 1, researchers in the Human Genome Project announced the complete sequencing of the DNA making up human chromosome 22.

Joint Genome Institute sequencing facility opens in Walnut Creek, CA.

Major Drug Firms Create Public SNP Consortium

The Billion Base Pair Celebration November 23, 1999. Bruce Alberts, President, National Academy of Sciences and early planner of the Genome Project; Francis Collins, Director, NHGRI; Secretary of HHS, Donna Shalala; Secretary of DOE, Bill Richardson. (Total Running Time: 01:09:45; Bandwidth: 146 Kbps)

HGP advances goal for obtaining a draft sequence of the entire human genome from 2001 to 2000.

Table 1.1 Human single gene taits(1994)

1.7 다인자성 질환

ㆍGalton 은 지능, 신체규격 등과 같이 멘델법칙에 맞지 않는 인간 형질을 연구함

ㆍ멘델 지지자와 Galton 지지자들 사이에 논쟁을 통계학자인 Fisher가 중재하여, 그러한 유전은 많은 유전자 쌍에 의해 지배를 받으며, 각 유전자들의 부가적 효과로 형질이 나타난다고 설명함.

ㆍ불연속적인 다인자성 유전의 경우는 threshold 효과에 의해 설명됨.

※threshold 효과에 대해 공부 합시다

ㆍ많은 인간 유전형질은 유전인자와 환경적 요소와 상호작용의 결과이다.

ㆍ다인자성 유전에 관여하는 유전자 및 환경적인 요소에 대해 잘 알려져 있지 않으므로, 당뇨병, 치매, 류마티스, 조기혈관질환 등에 관여하는 유전자를 밝히는 데 역점을 두고 있다.

1.8 체세포 유전 질환

ㆍ모든 암은 돌연변이가 축적되어 발생한다.

ㆍ이러한 돌연변이는 수정 후에 일어나며, 체세포에 국한되어져 일어난다.

ㆍBoveri 는 암이 염색체 이상으로 인해 발생한다는 의견을 제시했고, 실제로, 1973년 염색체 전좌(Philadelphia 염색체, 9번과 22번 사이의 전좌)가 백혈병 환자에서 발견되었다.

Definition of Philadelphia chromosome (Ph)(출처: http://www.medterms.com/script/main/art.asp?articlekey=4870)

Philadelphia chromosome (Ph): The chromosome abnormality that causes chronic myeloid leukemia (CML). Abbreviated as the Ph chromosome.

The Ph chromosome is an abnormally short chromosome 22 that is one of the two chromosomes involved in a translocation (an exchange of material) with chromosome 9. This translocation takes place in a single bone marrow cell and, through the process of clonal expansion (the production of many cells from this one mutant cell), it gives rise to the leukemia.

The discovery in Philadelphia in 1960 of the Ph chromosome was a landmark. It was the first consistent chromosome abnormality found in any kind of malignancy. The discovery led to the identification in CML cells of the BCR-ABL fusion gene and its corresponding protein. ABL and BCR are normal genes on chromosomes 9 and 22, respectively. The ABL gene encodes a tyrosine kinase enzyme whose activity is tightly regulated (controlled). In the formation of the Ph translocation, two fusion genes are generated: BCR-ABL on the Ph chromosome and ABL-BCR on the chromosome 9 participating in the translocation. The BCR-ABL gene encodes a protein with deregulated (uncontrolled) tyrosine kinase activity. The presence of this protein in the CML cells is strong evidence of its pathogenetic (disease-causing) role. The efficacy in CML of a drug that inhibits the BCR-ABL tyrosine kinase has provided the final proof that the BCR-ABL oncoprotein is the unique cause of CML.

The Ph chromosome is also found in a form of acute lymphoblastic leukemia (ALL). It seems highly probable that this form of ALL is due to the same chromosomal and molecular mechanisms as CML.

Philadelphia chromosome The hallmark of chronic myeloid leukemia (CML). The Philadelphia (Ph) chromosome is an abbreviated chromosome 22 that was shortchanged in an a reciprocal exchange of material with chromosome 9. This translocation occurs in a cell in the bone-marrow cell, and causes CML It is also found in a form of acute lymphoblastic leukemia (ALL). On a molecular level the Philadelphia chromosome translocation results in the production of a fusion protein. A large portion of a proto-oncogene, called ABL, on chromosome 9 is translocated to the BCR gene on chromosome 22. The two gene segments are fused and ultimately produce a chimeric protein that is larger than the normal ABL protein. The malignant state is a consequence of this process. Understanding this process led to the development of the drug imatinib mesylate (Gleevec) the first in a new class of genetically targeted agents, a major advance in cancer treatment

BCR (gene)(출처: http://en.wikipedia.org/wiki/BCR_(gene))

The breakpoint cluster region protein (BCR) also known as renal carcinoma antigen NY-REN-26 is a protein that in humans is encoded by the BCR gene. BCR is one of the two genes in the BCR-ABL complex, which is associated with the Philadelphia chromosome. Two transcript variants encoding different isoforms have been found for this gene.

Function

Although the BCR-ABL fusion protein has been extensively studied, the function of the normal BCR gene product is not clear. The protein has serine/threonine kinase activity and is a GTPase-activating protein for RAC1 and CDC42.[1]

ㆍ그 후 여러 종류의 암에서 염색체 이상이 발견됨.

ㆍ이러한 염색체 이상은 암으로 진행하는 데 관여하는 유전자를 찾아내는 데 중요한 요소로 사용되어 많은 유전자들이 cloning 되어 암의 발생기전 이해와 암 발생 성향 유전자를 갖는 사람을 찾아내는 수단으로 사용됨.

Table 1.2 Chronicles of medical genetics

2. 의학유전학의 임상적 응용

ㆍ감염질환들이 쉽게 치료하게 되고, 이전에는 출생 후 즉시 질식했을 지도 모를 영아들의 생명을 구하게 됨에 따라서 유전질환이 더욱더 중요한 질환의 일부가 됨

ㆍ이러한 이유로 인하여 유전질환에 대한 상담과 SCREENING TEST 등에 대한 요구가 증가하고 있다.

2.1 유전적 측정과 상담

ㆍ의학 유전학자들은 정확한 유전적 측정에 부가하여 자손 번식에 대한 것도 토론해야 한다.

ㆍ태아 진단이 발전함에 따라서 선택적으로 유산을 시킬 수 있게 되었고, 이러한 것이 유전학적 상담에 대한 요구가 증가된 요인이 되었다.

ㆍ심각한 질병을 앓고 있는 부부에게 건강한 아이를 낳을 수 있는 가능성을 부여함

2.2 태아진단

ㆍ양수검사에 의한 염색체분석은 일상적으로 행해지며, 200가지 이상의 염색체 이상이 알려졌다.

Definition

Amniotic fluid surrounds the baby during pregnancy. Amniocentesis is the removal of a small amount of this fluid for testing.

Amniocentesis

Copyright © Nucleus Medical Media, Inc.

ㆍ양수검사와 조기 융모막 검사는 대사성 이상 질환의 진단에도 사용됨.

Procedure - Chorionic Villus Sampling:(출처: http://www.umm.edu/pregnancy/000242.htm)

Chorionic villi are microscopic projections that line the chorion, the outermost layer of the embryonic sac. Surgeons sample these projections for genetic testing because they contain the same genetic material as a fetus.

If you are at risk for delivering a baby with genetic abnormalities, your health-care provider may recommend this prenatal test, which is performed at 10 to 12 weeks gestation to find out a fetus' genetic makeup.

Procedure - Chorionic Villus Sampling:

To take a chorionic villus sample, your surgeon either enters the uterus through the cervix (transcervical procedure) or through the abdomen (transabdominal procedure). The fetus' position in the uterus determines which procedure the surgeon uses.

Procedure - Chorionic Villus Sampling:

If your surgeon uses a transcervical procedure, he opens your vagina with a speculum and eases a thin catheter through it and your cervix.

Your surgeon then moves the catheter to the chorionic villi with the guidance of an ultrasound. He checks the fetus' position on the ultrasound screen so he can maneuver the catheter within the uterus without harming the fetus.

Procedure - Chorionic Villus Sampling:

If your surgeon uses the transabdominal procedure, it will be very similar to amniocentesis. He inserts a needle through your abdomen and uterus to the chorionic villi. As with the transcervical procedure, your surgeon uses ultrasound to determine the fetus' position to help guide the needle safely to the chorionic villi.

Procedure - Chorionic Villus Sampling:

Once the catheter or needle reaches the chorionic villi, your surgeon withdraws a small sample and carefully removes it from the uterus.

You should receive Rh immune globulin (RHIG) at the time of CVS if you are an Rh-negative unsensitized patient.

The sample is sent to a laboratory. How the lab technicians handle the sample depends on the genetic abnormalities they are looking for and the type of technology they use. They will extract chromosomes from the sample's cells to find out if your fetus is carrying any genetic abnormalities.

In most cases, your health-care provider will have your test results back within two weeks. The results can help you and your partner decide whether to carry the pregnancy to term, or how to prepare for the baby you will deliver.

ㆍ태아진단은 DNA 분석에 의해서도 수행될 수 있다. DNA 분석은 200 가지 이상의 단일 유전자 이상 질환을 진단하는데 사용되고, 낭포성섬유증, fragile X syndrome, Duchenne muscular dystrophy(근 위축증) 등의 진단에 널리 사용되고 있다.

Understanding Cystic Fibrosis: The Basics(출처: http://children.webmd.com/guide/understanding-cystic-fibrosis-basics)

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Cystic fibrosis is an incurable genetic disease that affects the glands that produce mucus and sweat. It causes mucus to become thick and sticky.

As the mucus builds up, it can block airways in the lungs. This makes it increasingly difficult to breathe.

Understanding Cystic Fibrosis

Find out more about cystic fibrosis:

Basics

Symptoms

Diagnosis and Treatment

Mucus buildup also encourages the growth of bacteria. This can cause frequent, damaging infections in the lungs.

Mucus buildup can also prevent necessary digestive enzymes from reaching your intestines. The body needs these enzymes to process the nutrients in the food that you eat, such as vitamins and minerals.

People with cystic fibrosis also lose large amounts of salt when they sweat. This can cause an unhealthy imbalance of minerals in your blood. It can lead to:

Dehydration

Fatigue

Weakness

Increased heart rate

Low blood pressure

Heat stroke

Death in rare cases

About 30,000 Americans have cystic fibrosis. Each year about 1,000 new cases are diagnosed.

Nowadays people with cystic fibrosis generally live into their mid-30s. Sixty years ago, the disease killed most people before they reached elementary school.

What Causes Cystic Fibrosis?

Cystic fibrosis is a genetic disease. That means you are born with it, having inherited the abnormal gene that causes it from your parents.

Both parents must be carriers of the gene that causes the disease. Twenty-five percent of the children of such parents will be diagnosed with cystic fibrosis.

Boys and girls are equally likely to get the disease. About 10 million Americans carry the gene and do not know it. Many more whites get the disease than people of other races.

What Are the Symptoms of Cystic Fibrosis?

The symptoms of cystic fibrosis may not always be apparent at birth. Occasionally, they are mild enough to go unnoticed. Over time the symptoms become more severe and require special treatment. The most common symptoms include:

Salty-tasting skin

Persistent cough that produces phlegm

Lung infections caused by bacteria

Frequent cases of sinusitis, bronchitis, or pneumonia

Shortness of breath and wheezing

Growths in the nose (nasal polyps)

Poor weight gain and growth

Persistent diarrhea or bulky, foul-smelling, and greasy stool

Over time, the symptoms of cystic fibrosis will likely worsen and may include:

Pancreatitis, a painful inflammation of the pancreas

Liver disease

Diabetes

Gallstones

How Is Cystic Fibrosis Diagnosed?

A genetic test, which can be done before birth, will determine if your baby has a faulty CFTR gene. This is the gene responsible for cystic fibrosis.

Every state now screens newborns for cystic fibrosis. Blood testing will show whether your baby's pancreas is functioning the way it should.

If the testing indicates possible cystic fibrosis, a sweat test will be given. A high salt level in your baby's sweat will confirm the diagnosis.

After diagnosis, the doctor may order additional tests. These tests will measure lung function and check for bacterial growth in the sputum, or spit. The tests will help determine how far the disease has advanced.

Fragile X syndrome(출처; http://en.wikipedia.org/wiki/Fragile_X_syndrome)

Fragile X syndrome (FXS), Martin–Bell syndrome, or Escalante's syndrome (more commonly used in South American countries), is a genetic syndrome that is the most widespread single-gene cause of autism and inherited cause of mental retardation among boys. It results in a spectrum of intellectual disabilities ranging from mild to severe as well as physical characteristics such as an elongated face, large or protruding ears, and large testes (macroorchidism), and behavioral characteristics such as stereotypic movements (e.g. hand-flapping), and social anxiety.

Fragile X syndrome is associated with the expansion of the CGG trinucleotide repeat affecting the Fragile X mental retardation 1 (FMR1) gene on the X chromosome, resulting in a failure to express the fragile X mental retardation protein (FMRP), which is required for normal neural development. Depending on the length of the CGG repeat, an allele may be classified as normal (unaffected by the syndrome), a premutation (at risk of fragile X associated disorders), or full mutation (usually affected by the syndrome).[1] A definitive diagnosis of fragile X syndrome is made through genetic testing to determine the number of CGG repeats. Testing for premutation carriers can also be carried out to allow for genetic counseling.

There is currently no drug treatment that has shown benefit specifically for fragile X syndrome. However, medications are commonly used to treat symptoms of attention deficit and hyperactivity, anxiety, and aggression. Supportive management is important in optimizing functioning in individuals with fragile X syndrome, and may involve speech therapy, occupational therapy, and individualized educational and behavioral programs.

ㆍ그러나 이러한 염색체 분석, DNA 분석, 생화학적분석 등으로 진단할 수 없는 선천성 기형들이 있으며, 이러한 것들은 초음파로 진단할 수 있다.

2.3 유전병의 치료와 예방

ㆍ유전병을 치료할 수 있는 가능성이 많아지고 있으며, 1990년에는 adenosine deaminase(purine metabolism, severe combined immunodeficiency, SCID 초래) 결핍증에 대한 유전자 치료가 시도되기도 했다.

ㆍ1994년까지 200가지 이상의 유전자 치료의 임상적용이 허락 되었다.

ㆍ대부분의 부모들은 그들이 질병이 걸린 아이를 출산하기 전에는 그 위험성을 모르고 있다.

ㆍ따라서, 엄마의 혈청 alpha-fetoprotein(estradiol 과 결합, 지방산 운반, 태아에서 생산, 성인의 경우 낮음,) 등을 측정하여 neural tube defect(NTD, 신경관 결함) 등의 태아 진단이 중요하게 인식 되었고(NTD의 경우 산모의 혈중 AFP농도 높음, down 증후군의 경우 산모의 혈중 AFP농도가 낮음) phenylketonuria 등의 경우에 있어서는 신생아를 진단하여 치료함으로서 정상발육이 되도록 할 수 있다.

Phenylketonuria(출처: http://en.wikipedia.org/wiki/Phenylketonuria)

Phenylketonuria (PKU) is an autosomal recessive metabolic genetic disorder characterized by a mutation in the gene for the hepatic enzyme phenylalanine hydroxylase (PAH), rendering it nonfunctional.[1]:541 This enzyme is necessary to metabolize the amino acid phenylalanine (Phe) to the amino acid tyrosine. When PAH activity is reduced, phenylalanine accumulates and is converted into phenylpyruvate (also known as phenylketone), which is detected in the urine.[2]

Untreated PKU can lead to mental retardation, seizures, and other serious medical problems.[3] The mainstream treatment for classic PKU patients is a strict PHE-restricted diet supplemented by a medical formula containing amino acids and other nutrients.[4] In the United States, the current recommendation is that the PKU diet should be maintained for life.[5] Patients who are diagnosed early and maintain a strict diet can have a normal life span with normal mental development. However, recent research suggests that neurocognitive, psychosocial, quality of life, growth, nutrition, bone pathology are slightly suboptimal if diet is not supplemented with amino acids.[6]

Contents

1 History

2 Screening and presentation

3 Pathophysiology

3.1 Classical PKU

3.2 Tetrahydrobiopterin-deficient hyperphenylalaninemia

4 Metabolic pathways

5 Treatment

6 Maternal phenylketonuria

7 Incidence

8 See also

9 References

10 External links

History

Phenylketonuria was discovered by the Norwegian physician Ivar Asbjørn Følling in 1934[7] when he noticed hyperphenylalaninemia (HPA) was associated with mental retardation. In Norway, this disorder is known as Følling's disease, named after its discoverer.[8] Dr. Følling was one of the first physicians to apply detailed chemical analysis to the study of disease. His careful analysis of the urine of two affected siblings led him to request many physicians near Oslo to test the urine of other affected patients. This led to the discovery of the same substance he had found in eight other patients. He conducted tests and found reactions that gave rise to benzaldehyde and benzoic acid, which led him to conclude that the compound contained a benzene ring. Further testing showed the melting point to be the same as phenylpyruvic acid, which indicated that the substance was in the urine. His careful science inspired many to pursue similar meticulous and painstaking research with other disorders. It was recently suggested that PKU may resemble amyloid diseases, such as Alzheimer's disease and Parkinson's disease, due to the formation of toxic amyloid-like assemblies phenylalanine.[9]

Screening and presentation

Blood is taken from a two-week old infant to test for phenylketonuria

PKU is commonly included in the newborn screening panel of most countries, with varied detection techniques. Most babies in developed countries are screened for PKU soon after birth.[10] Screening for PKU is done with bacterial inhibition assay (Guthrie test), immunoassays using fluorometric or photometric detection, or amino acid measurement using tandem mass spectrometry (MS/MS). Measurements done using MS/MS determine the concentration of Phe and the ratio of Phe to tyrosine, both of which will be elevated in PKU.[11]

If a child is not screened during the routine newborn screening test (typically performed 2 – 7 days after birth, using samples drawn by neonatal heel prick), the disease may present clinically with seizures, albinism (excessively fair hair and skin), and a "musty odor" to the baby's sweat and urine (due to phenylacetate, one of the ketones produced). In most cases, a repeat test should be done at approximately two weeks of age to verify the initial test and uncover any phenylketonuria that was initially missed.

Untreated children are normal at birth, but fail to attain early developmental milestones, develop microcephaly, and demonstrate progressive impairment of cerebral function. Hyperactivity, EEG abnormalities and seizures, and severe learning disabilities are major clinical problems later in life. A "musty or mousy" odor of skin, hair, sweat and urine (due to phenylacetate accumulation); and a tendency to hypopigmentation and eczema are also observed.

In contrast, affected children who are detected and treated are less likely to develop neurological problems or have seizures and mental retardation, though such clinical disorders are still possible.

Pathophysiology

Classical PKU

Classical PKU is caused by a mutated gene for the enzyme phenylalanine hydroxylase (PAH), which converts the amino acid phenylalanine to other essential compounds in the body. Other non-PAH mutations can also cause PKU. This is an example of non-allelic genetic heterogeneity. The PAH gene is located on chromosome 12 in the bands 12q22-q24.1. More than 400 disease-causing mutations have been found in the PAH gene. PAH deficiency causes a spectrum of disorders, including classic phenylketonuria (PKU) and hyperphenylalaninemia (a less severe accumulation of phenylalanine).[12]

PKU is known to be an autosomal recessive genetic disorder. This means both parents must have at least one mutated allele of the PAH gene. The child must inherit both mutated alleles, one from each parent. Therefore, it is possible for a parent with the disease to have a child without it if the other parent possesses one functional allele of the gene for PAH. Yet, a child from two parents with PKU will inherit two mutated alleles every time, and therefore the disease.

Phenylketonuria can exist in mice, which have been extensively used in experiments into finding an effective treatment for it.[13] The macaque monkey's genome was recently sequenced, and the gene encoding phenylalanine hydroxylase was found to have the same sequence that, in humans, would be considered the PKU mutation.[14]

Tetrahydrobiopterin-deficient hyperphenylalaninemia

A rarer form of hyperphenylalaninemia occurs when PAH is normal, but there is a defect in the biosynthesis or recycling of the cofactor tetrahydrobiopterin (BH4) by the patient.[15] This cofactor is necessary for proper activity of the enzyme . The coenzyme (called biopterin) can be supplemented as treatment. Those who suffer from PKU must be supplemented with tyrosine to account for phenylalanine hydroxylase deficiency in converting phenylalanine to tyrosine sufficiently. Dihydrobiopterin reductase activity is to replenish quinonoid-dihydrobiopterin back into its tetrahydrobiopterin form, which is an important cofactor in many metabolic reactions in amino acid metabolism. Those with this deficiency may produce sufficient levels of phenylalanine hydroxylase, but since tetrahydrobiopterin is a cofactor for phenylalanine hydroxylase activity, deficient dihydrobiopterin reductase renders any phenylalanine hydroxylase enzyme produced unable to use phenylalanine to produce tyrosine. Tetrahydrobiopterin is also a cofactor in the production of L-DOPA from tyrosine and 5-Hydroxy-L-Tryptophan from tryptophan, which must also be supplemented as treatment in addition to the supplements for classical PKU.

Levels of dopamine can be used to distinguish between these two types. Tetrahydrobiopterin is required to convert phenylalanine to tyrosine, but it is also required to convert tyrosine to L-DOPA (via the enzyme tyrosine hydroxylase), which in turn is converted to dopamine. Low levels of dopamine lead to high levels of prolactin. By contrast, in classical PKU, prolactin levels would be relatively normal. Tetrahydrobiopterin deficiency can be caused by defects in four different genes. These types are known as HPABH4A, HPABH4B, HPABH4C, and HPABH4D.[16]

Metabolic pathways

The enzyme phenylalanine hydroxylase normally converts the amino acid phenylalanine into the amino acid tyrosine. If this reaction does not take place, phenylalanine accumulates and tyrosine is deficient. Excessive phenylalanine can be metabolized into phenylketones through the minor route, a transaminase pathway with glutamate. Metabolites include phenylacetate, phenylpyruvate and phenethylamine.[17] Elevated levels of phenylalanine in the blood and detection of phenylketones in the urine is diagnostic, however most patients are diagnosed via newborn screening.

Phenylalanine is a large, neutral amino acid (LNAA). LNAAs compete for transport across the blood–brain barrier (BBB) via the large neutral amino acid transporter (LNAAT). If phenylalanine is in excess in the blood, it will saturate the transporter. Excessive levels of phenylalanine tend to decrease the levels of other LNAAs in the brain. However, as these amino acids are necessary for protein and neurotransmitter synthesis, Phe buildup hinders the development of the brain, causing mental retardation.[18]

Treatment

If PKU is diagnosed early enough, an affected newborn can grow up with normal brain development, but only by managing and controlling Phe levels through diet, or a combination of diet and medication. Optimal health ranges (or "target ranges") are between 120 and 360 µmol/L, and aimed to be achieved during at least the first 10 years.[19] When Phe cannot be metabolized by the body, abnormally high levels accumulate in the blood and are toxic to the brain. When left untreated, complications of PKU include severe mental retardation, brain function abnormalities, microcephaly, mood disorders, irregular motor functioning, and behavioral problems such as attention deficit hyperactivity disorder.

All PKU patients must adhere to a special diet low in Phe for optimal brain development. "Diet for life" has become the standard recommended by most experts. The diet requires severely restricting or eliminating foods high in Phe, such as meat, chicken, fish, eggs, nuts, cheese, legumes, milk and other dairy products. Starchy foods, such as potatoes, bread, pasta, and corn, must be monitored. Infants may still be breastfed to provide all of the benefits of breastmilk, but the quantity must also be monitored and supplementation for missing nutrients will be required. The sweetener aspartame, present in many diet foods and soft drinks, must also be avoided, as aspartame contains two amino acids: phenylalanine and aspartic acid.

Supplementary infant formulas are used in these patients to provide the amino acids and other necessary nutrients that would otherwise be lacking in a low-phenylalanine diet. As the child grows up these can be replaced with pills, formulas, and specially formulated foods. (Since Phe is necessary for the synthesis of many proteins, it is required for appropriate growth, but levels must be strictly controlled in PKU patients.) In addition, tyrosine, which is normally derived from phenylalanine, must be supplemented.

The oral administration of tetrahydrobiopterin (or BH4) (a cofactor for the oxidation of phenylalanine) can reduce blood levels of this amino acid in certain patients.[20][21] The company BioMarin Pharmaceutical has produced a tablet preparation of the compound sapropterin dihydrochloride (Kuvan), which is a form of tetrahydrobiopterin. Kuvan is the first drug that can help BH4-responsive PKU patients (defined among clinicians as about 1/2 of the PKU population) lower Phe levels to recommended ranges.[22] Working closely with a dietitian, some PKU patients who respond to Kuvan may also be able to increase the amount of natural protein they can eat.[23] After extensive clinical trials, Kuvan has been approved by the FDA for use in PKU therapy. Some researchers and clinicians working with PKU are finding Kuvan a safe and effective addition to dietary treatment and beneficial to patients with PKU.[24][25]

Several other therapies are currently under investigation, including gene therapy, large neutral amino acids, and enzyme substitution therapy with phenylalanine ammonia lyase (PAL). In the past, PKU-affected people were allowed to go off diet after approximately eight, then 18 years of age. Today, most physicians recommend PKU patients must manage their Phe levels throughout life.

Maternal phenylketonuria

Phenylketonuria is inherited in an autosomal recessive fashion

For women with PKU, it is essential for the health of their children to maintain low Phe levels before and during pregnancy.[26] Though the developing fetus may only be a carrier of the PKU gene, the intrauterine environment can have very high levels of phenylalanine, which can cross the placenta. The child may develop congenital heart disease, growth retardation, microcephaly and mental retardation as a result.[27] PKU-affected women themselves are not at risk of additional complications during pregnancy.

In most countries, women with PKU who wish to have children are advised to lower their blood Phe levels (typically to between 2 and 6 micromol/deciliter) before they become pregnant, and carefully control their levels throughout the pregnancy. This is achieved by performing regular blood tests and adhering very strictly to a diet, in general monitored on a day-to-day basis by a specialist metabolic dietitian. In many cases, as the fetus' liver begins to develop and produce PAH normally, the mother's blood Phe levels will drop, requiring an increased intake to remain within the safe range of 2-6 micromol/dL. The mother's daily Phe intake may double or even triple by the end of the pregnancy, as a result. When maternal blood Phe levels fall below 2 micromol/dL, anecdotal reports indicate that the mothers may suffer adverse effects, including headaches, nausea, hair loss, and general malaise. When low phenylalanine levels are maintained for the duration of pregnancy, there are no elevated levels of risk of birth defects compared with a baby born to a non-PKU mother.[28] Babies with PKU may drink breast milk, while also taking their special metabolic formula. Some research has indicated an exclusive diet of breast milk for PKU babies may alter the effects of the deficiency, though during breastfeeding the mother must maintain a strict diet to keep her Phe levels low. More research is needed. US scientist announced in June 2010 that they would be conducting a thorough investigation on the mutation of genes in the human genome. Their top priority is PKU, as it has become increasingly common, and sufferers often bear children who will be carriers of the recessive gene, and may themselves live past the age of sixty.

Incidence

The mean incidence of PKU varies widely in different human populations. United States Caucasians are affected at a rate of 1 in 10,000.[29] Turkey has the highest documented rate in the world, with 1 in 2,600 births, while countries such as Finland and Japan have extremely low rates with fewer than one case of PKU in 100,000 births.

Country	Incidence of PKU
China	1 in 18,000[30]
Finland	<1 in 100,000[31]
Ireland	1 in 4,500[32]
Japan	1 in 120,000[33]
Korea	1 in 41,000[34]
Norway	1 in 13,000[35]
Turkey	1 in 2,600
India	1 in 18,300
United States	1 in 15,000 [36]

References

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^ Online 'Mendelian Inheritance in Man' (OMIM) 261640

^ Michals, K., Matalon, R. (1985). "Phenylalanine metabolites, attention span and hyperactivity". American Journal of Clinical Nutrition 42 (2): 361–5. PMID 4025205.

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^ Levy H, Burton B, Cederbaum S et al. (2007). "Recommendations for evaluation of responsiveness to tetrahydrobiopterin (BH(4)) in phenylketonuria and its use in treatment". Mol Genet Metab 92 (4): 287–291. doi:10.1016/j.ymgme.2007.09.017. PMID 18036498.

^ Levy HL, Milanowski A, Chakrapani A, Cleary M, Lee P, Trefz FK et al. (2007). "Efficacy of sapropterin dihydrochloride (tetrahydrobiopterin, 6R-BH4) for reduction of phenylalanine concentration in patients with phenylketonuria: a phase III randomised placebo-controlled study". Lancet 370 (9586): 504–510. doi:10.1016/S0140-6736(07)61234-3. PMID 17693179.

^ Lee P, Treacy E, Crombez E et al. (2008). "Safety and efficacy of 22 weeks of treatment with sapropterin dihydrochloride in patients with phenylketonuria". Am J Med Genet 146A (22): 2851–2859. doi:10.1002/ajmg.a.32562. PMID 18932221.

^ Lee, P.J., Ridout, D., Walker, J.H., Cockburn, F., (2005). "Maternal phenylketonuria: report from the United Kingdom Registry 1978–97". Archives of Disease in Childhood 90 (2): 143–146. doi:10.1136/adc.2003.037762. PMC 1720245. PMID 15665165. //www.ncbi.nlm.nih.gov/pmc/articles/PMC1720245/.

^ Rouse, B., Azen, B., Koch, R., Matalon, R., Hanley, W., de la Cruz, F., Trefz, F., Friedman, E., Shifrin, H. (1997). "Maternal phenylketonuria collaborative study (MPKUCS) offspring: Facial anomalies, malformations, and early neurological sequelae". American Journal of Medical Genetics 69 (1): 89–95. doi:10.1002/(SICI)1096-8628(19970303)69:1<89::AID-AJMG17>3.0.CO;2-K. PMID 9066890.

^ lsuhsc.edu Genetics and Louisiana Families

^ Bickel, H.;, Bachmann, C.; Beckers, R.; Brandt, N.J.; Clayton, B.E.; Corrado, G; et al. (1981). "Neonatal mass screening for metabolic disorders: summary of recent sessions of the committee of experts to study inborn metabolic diseases". public health committee, Eur. J. Pediatr. (137): 133–139.

^ Liu, S.R.; Zuo, Q.H. (1986). "Newborn screening for phenylketonuria in eleven districts". Chin. Med. J. 99: 113–118.

^ Guldberg, P., Henriksen, K. F., Sipila, I., Guttler, F., de la Chapelle, A. (1995). "Phenylketonuria in a low incidence population: molecular characterization of mutations in Finland". J. Med. Genet 32 (12): 976–978. doi:10.1136/jmg.32.12.976. PMC 1051781. PMID 8825928. //www.ncbi.nlm.nih.gov/pmc/articles/PMC1051781/.

^ DiLella, A. G., Kwok, S. C. M., Ledley, F. D., Marvit, J., Woo, S. L. C. (1986). "Molecular structure and polymorphic map of the human phenylalanine hydroxylase gene". Biochemistry 25 (4): 743–749. doi:10.1021/bi00352a001. PMID 3008810.

^ Aoki, K.; Wada, Y. (1988). "Outcome of the patients detected by newborn screening in Japan". Acta Paediatr. Jpn. 30 (4): 429–434.

^ Lee, D.H.; Koo, S.K.; Lee, K.S.; Yeon, Y.J.; Oh, H.J.; Kim, S.W.;Lee, S.J. ; Kim, S.S.; Lee, J.E.; Jo, I.; Jung, S.C. (2004). "The molecular basis of phenylketonuria in Koreans". J. Hum. Genet. 49 (1): 617–621.

^ www.rikshospitalet.no

^ "Medscape: Medscape Access". Emedicine.medscape.com. http://emedicine.medscape.com/article/947781-overview. Retrieved 2013-01-26.

ㆍ장래는 인구집단의 진단, 태아진단, 신생아 진단, 임신전 진단 등을 통하여 질병의 빈도를 줄일 수 있을 것이다.