제 5 장 Gametogenesis

ㆍ생식선에서 일어나며, 체세포의 이배체 염색체가 반으로 줄어들어 각 gamete에 각 상동염색체의 하나씩이 들어가게 된다. 이러한 과정은 감수분열에 의해 일어남.

1. 감수분열

ㆍ감수분열은 DNA 복제 후 두 번의 연속적인 분열로 이루어짐.

Figure 5.1 Meiosis

1.1 제 1 감수분열

ㆍ분열 전기는 5단계로 나눔.

ㆍleptotene :염색체 출현. 각 염색체는 sister chromatid 로 되어 있음.

Figure 5.2 Leptotene(spermatocyte)

ㆍzygotene : 상동염색체 짝짓기가 일어남. 짝짓기 기작은 모르나, 반복서열 지역이 초기 배열에 관여할 것으로 추정. X와 Y 염색체는 짧은 팔의 끝부분에서 짝짓기 함. XY 짝은 pachytene 초기에 응축되어지므로, 짝짓기 안된 부위의 교차를 방지하게 되는 것으로 생각됨.

Figure 5.3 Zygotene

Figure 5.4 Homology of banding pattern from meiotic and mitotic chromosome

ㆍpachytene : 염색체가 응축됨. 각 염색체는 두개의 chromatid 로 구성되고

Figure 5.5 Pachytene

이가 염색체는 tetrad(4개의 chromatid)로 구성된다. acrocentric chromosome 들의 satellite 들이 서로 뭉치는 형태가 보이는데 이것은 비 상동염색체 사이의 homologous repetitive sequence에 의한 synapsis 이거나 아니면 satellite 들이 모여서 nucleolus organization 에 관여하기 때문인 것으로 보인다.

ㆍDiplotene : 매우 짧은 기간이다. 이 기간에는 이가염색체가 분리되기 시작하나, 각 염색체의 두 chromatid 들은 centromere에 붙어 있다. 각 이가염색체의 각 여색체의 chromatid들이 여러 군데에서 붙어 있다. 이것을 chiasmata라고 하며, 교차가 일어나는 부위이다. 평균 한 남성 세포에서 52개의 chiasmata 가 관찰된다. 이것은 평균 한 염색체 팔에 한번 이상의 chiasma 가 있다는 것을 의미한다. XY 짝의 경우 작은 부분에 걸쳐서 붙어 있으며, 그 부분에서 교차가 일어난다. 이 지역은 성과 관련이 없는 다시 말하면 상염색체성 유전을 나타낸다.

ㆍDiakinesis : 분열 전기의 마지막 단계로 염색체가 더 꼬여서 진하게 염색이 된다.

ㆍ중기는 핵막이 사라지면서 시작된다. 염색체가 적도면으로 이동한다.

ㆍ후기에는 이가염색체의 두 염색체가 떨어져서 각 극 쪽으로 이동한다.

ㆍ세포질이 분활되고 각 세포는 23개의 염색체를  갖게되며, 각 염색체는 한 쌍의 chromatid를 갖게 된다. 한 염색체를 이루는 두 chromatid는 교차의 결과에 따라서 다르다.

Figure 5.6 Early diakinesis

Figure 5.7 Diagram of crossing over

Figure 5.8 XY pairing at pachytene(top)

Figure 5.9 Single condensed X(second meiotic metaphase)

1.2 제 2 감수 분열

ㆍ제 2 감수분열은 간기 없이 진행되며, 유사분열과 비슷하게 진행됨. 즉, centromere가 분리되어 sister chromatid가 반대 극으로 이동한다. 단지, 유사분열에서보다 염색체가 더 꼬여 있는 점이 다르다.

※ 유사분열과 감수분열의 차이점을 정리합시다.

Table 5.1 Mitosis vs meiosis

ㆍ염색체가 독립적으로 분리되어지므로 각 양친으로부터 나오는 gamete에 있는 염색체는  223 가지의 서로 다른 조합을 갖게 된다. 그러므로, 수정란의 경우는 246 가지의 조합이 가능하다. 그러나 실제로는 교차에 의해 더 다양한 변이가 있을 수 있다. 만약 한 염색체에 평균 한번의 교차가 일어나고, 엄마와 아빠의 대립인자의 10%가 다르다고 할때, 가능한 수정란의 종류는 6x1043 이 된다.

ㆍ감수분열의  3가지 중요한 결과

-gamete는 각 상동염색체 중 하나씩만을 갖게 된다.

-부모로부터 받은 상동염색체는 독립적으로 분리 되어진다.

-교차로 인하여 유전적 변이를 증가시켜서 각각 유일성이 있는 gamete를 만든다.

2. 정자형성

ㆍ정자형성은 세정관에서 일어난다. 사춘기에 세정관의 spermatogonia(정원세포)로부터 정자형성이 시작되어 제 1차 정모세포로 된다.

ㆍ제 1차 정모세포는 제 1 감수분열을 진행하여 두 개의 제 2차 정모세포가 되며, 각 세포는 23개의 염색체를 갖게 된다..

ㆍ  제 2차 정모세포는 즉시 제 2감수분열을 진행하여 spermatid(정세포)를 형성한다.

ㆍspermatid는 성숙하여 sperm(정자)가 되며, 정원세포로부터 정자가 형성되는 과정은 61일이 걸린다.

ㆍ보통 정액 1ml에 5천만 -1억 개의 정자가  들어 있다. 나이가 들면서 정자 생산은 줄어들며, 돌연변이도 증가한다.

3.난자형성

ㆍ정자형성과는 달리, 난자형성과정은 출생시에 상당히 진해되어 있다.

ㆍ primordial germ cell(원시난원세포)에서 유래된 oogonia(난원세포)는 각 난포의 중심에 위치한다. 태아 3개월째에 난원세포는 제 1 난모세포로 되며, 이들 중 일부는 제 1 감수분열의 전기에 들어가 있는 상태가 된다.  제 1 난모세포는 분열전기에서 멈춘 상태로 성적 성숙기 까지 유지된다.

ㆍ성적 성숙기 이후에는 각 난포가 성숙하여 난자를 나팔관으로 방출(배란)함으로서 제 1 감수분열이 끝난다.

ㆍ제 1 감수분열은 세포질의 부등분활에 의해 제 2난모세포는 대부분의 세포질을 받게 되고, 나머지 한 세포는 극체로 된다.

ㆍ제 2 감수분열은 나팔관에서 수정이 되고 나서 완성되며, 성숙한 난자와 제 2 극체가 형성된다. 이 단계에서 제 1 극체도 분열하여 두개의 극체로 된다. 감수분열이 4개의 정자를 생산하는 정자형성과는 다르게 난자형성은 하나의 난자를 생산한다.

ㆍ5개월 된 여자 태아의 생식세포는 6.8 X 103이지만 출생시에는 2 X 106, 사춘기에는 200000개 이하가 된다. 그 중 400 정도가 배란된다.

Figure 5.10 Spermatogenesis

Figure 5.11 Oogenesis

ㆍ너무 오랬동안 휴지기를 지내기 때문에 나이든 엄마의 경우 상동염색체의 불분리가 일어날 수 있다.

4. 수정

ㆍ수정은 일반적으로 나팔관에서 일어남. 정자가 침입하면, 화학적변화가 생겨 다른 정자의 침임을 방어하고, 침입한 정자는 pronucleus로 된다. 이 시기에 난자가 제2 감수분열을 마치게 되어 여성 pronucleus를 형성한다. 이 두 핵이 융합하여 난자가 형성된다.

Pronucleus

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The process of fertilization in the ovum of a mouse.

A pronucleus (plural: pronuclei) is the nucleus of a sperm or an egg cell during the process of fertilization, after the sperm enters the ovum, but before they fuse. Sperm and egg cells are haploid, meaning they carry half the number of chromosomes. When the pronucleus of a sperm fuses with the pronucleus of an egg, their chromosomes combine and become part of a single diploid nucleus in the resulting embryo, containing a full set of chromosomes.

The appearance of two pronuclei is the first sign of successful fertilization as observed during in vitro fertilisation, and is usually observed 18 hours after insemination or ICSI. The zygote is then termed a two-pronuclear zygote (2PN). Two-pronuclear zygotes transitioning through 1PN or 3PN states tend to develop into poorer-quality embryos than ones who remain 2PN throughout development,[1] and may be significant in embryo selection in IVF.

References

^ Reichman DE, Jackson KV, Racowsky C (May 2009). "Incidence and development of zygotes exhibiting abnormal pronuclear disposition after identification of two pronuclei at the fertilization check". Fertil. Steril. 94 (3): 965–970. doi:10.1016/j.fertnstert.2009.04.018. PMID 19476942

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

ㆍ수정란은 분열을 계속하여 신생아의 경우 2 X 1012 세포로 되고, 성인은 5 X 1012 세포로 된다.

Table 5.2 Embryonic and fetal milestone

5. Lyonization

ㆍ각 여성세포에 있는 두 개의 X 염색체 중 하나의 염색체가 불활성화 되는 과정을 lyonization이라고 한다. 이 과정은 모든 포유동물에 일어나며, 수정후 12일째의 영양아층(trophoblast)과 16일 째의 배아(5000 cell)에서 Barr body가 관찰되는 것으로 그것을 알 수 있다.

Blastocyst

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Blastocyst
Latin	blastocystis
Carnegie stage	3
Days	8
Precursor	Morula
Gives rise to	Gastrula, Inner cell mass
Code	TE E2.0.1.2.0.0.12
MeSH	Blastocyst

A human blastocyst, 5 days after fertilization.

A pig blastocyst. The bar is 0.1 mm.

The blastocyst is a structure formed in the early gestation of vertebrates. It is preceded by the morula. It possesses an inner cell mass (ICM), or embryoblast, which subsequently forms the embryo, and an outer layer of cells, or trophoblast, surrounding the inner cell mass and a fluid-filled cavity known as the blastocoele. The human blastocyst comprises 70-100 cells.

Blastocyst formation begins at day 5 after fertilization in humans.

Contents

1 Development cycle

2 Structure

3 References

4 External links

Development cycle

The blastocyst develops from the morula, a solid ball of about 16 undifferentiated, spherical cells within the zona pellucida. As cell division continues, the blastomeres change their shape and tightly align themselves against each other, forming the fluid-filled cavity called the blastocoele.

The cells now forming differentiate into two types, an inner-cell mass growing on the interior of the blastocele and cells growing on the exterior of it. In 24 to 48 hours, the zona pellucida breaches, referred to as hatching. This removes the constraint on the physical size of the cell mass.

The cells on the exterior of the blastocyst begin excreting an enzyme which erodes epithelial uterine lining and creates a site for implantation. The cells surrounding the blastocyst now destroy cells in the uterine lining, forming small pools of blood, which in turn stimulate the production of capillaries. This is the first stage in the growth of the placenta. The inner cell mass of the blastocyst divides rapidly, forming two layers. The top layer becomes the embryo, and cells from there occupy the amniotic cavity. At the same time, the bottom layer forms a small sac.

The blastocyst stage gives way to the gastrula with the formation of the primitive streak, after which when the embryonic cells change form and differentiate into three layers.

Structure

The blastocyst consists of two primary cell types:

the inner cell mass, also known as the "embryoblast"

the trophoblast, a layer of cells surrounding the inner cell mass and the blastocyst cavity (blastocoele).

The former is the source of embryonic stem cells and gives rise to all later structures of the adult organism. The latter combines with the maternal endometrium to form the placenta in eutherian mammals.

ㆍ불활성화는 체세포에서만 일어나며, 두 염색체 중 부계 X 혹은 모계 X 중

에서 무작위로 일어난다. 그러나, 한번 불활성화된 X 는 그 자손 세포에서도 동일한 X 가 불활성화되어 유지된다.

ㆍ이러한 lyonization 의 결과 여자와 남자의 X 염색체 유전자는 같은 수준으로 발현되게 된다. 남자의 X는 항상 발현되기 때문이다.(단지, X가 응축되어 있는 제 1 정모세포의 경우는 예외)

ㆍX 불활성화는 X 염색체의 거의 모든 유전자를 불활성화 하지만 예외가 있다. X와 Y 염색체 모두에 존재하는 유전자인 steroid sulphatase, amelogenin, ZFX 등은 예외이다. 그 외에도, 신장(키), Turner syndrome 관련 유전자들도 X-Y 상동성 유전자에 포함 될 것이라고 추정된다.

Steroid sulfatase

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Steroid sulfatase (or steryl-sulfatase), formerly known as arylsulfatase C, is a sulfatase enzyme involved in the metabolism of steroids. It is encoded by the STS gene.[1]

Contents

1 Function

2 Clinical significance

3 See also

4 References

5 Further reading

6 External links

Function

The protein encoded by this gene catalyzes the conversion of sulfated steroid precursors the free steroid. This includes sulfated androgens and sulfated estrogens. The encoded protein is found in the endoplasmic reticulum, where it is present as a homodimer.[1]

Clinical significance

A deficiency is associated with X-linked ichthyosis, a scaly-skin disease affecting roughly 1 in every 2,000-6,000 males.[2][3]

See also

dehydroepiandrosterone sulfate

estrone sulfate

References

1. ^ a b "Entrez Gene: STS steroid sulfatase (microsomal), arylsulfatase C, isozyme S". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=412.

^ Alperin ES, Shapiro LJ (August 1997). "Characterization of point mutations in patients with X-linked ichthyosis. Effects on the structure and function of the steroid sulfatase protein". J. Biol. Chem. 272 (33): 20756–63. doi:10.1074/jbc.272.33.20756. PMID 9252398. http://www.jbc.org/cgi/pmidlookup?view=long&pmid=9252398.

^ Ghosh D (December 2004). "Mutations in X-linked ichthyosis disrupt the active site structure of estrone/DHEA sulfatase". Biochim. Biophys. Acta 1739 (1): 1–4. doi:10.1016/j.bbadis.2004.09.003. PMID 15607112. http://linkinghub.elsevier.com/retrieve/pii/S0925-4439(04)00158-9.

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

Genes >

AMELX

On this page:

Name

Normal function

Genetic changes

Gene location

Additional information

Other names

About genes

Glossary definitions

Reviewed February 2007

What is the official name of the AMELX gene?

The official name of this gene is “amelogenin, X-linked.”

AMELX is the gene's official symbol. The AMELX gene is also known by other names, listed below.

Read more about gene names and symbols on the About page.

What is the normal function of the AMELX gene?

The AMELX gene provides instructions for making a protein called amelogenin, which is essential for normal tooth development. Amelogenin is involved in the formation of enamel, which is the hard, white material that forms the protective outer layer of each tooth. Enamel is composed mainly of mineral-containing crystals. These microscopic crystals are arranged in organized bundles that give enamel its strength and durability. Although the exact function of amelogenin is not well understood, it appears to separate and support the ribbon-like crystals as they grow. Amelogenin is removed from the developing crystals when it is no longer needed, leaving mature enamel that contains very little protein.

Studies suggest that small amounts of amelogenin may also be present in tissues other than developing tooth enamel. For example, amelogenin has been found in certain bone, bone marrow, and brain cells. The function of amelogenin in these tissues is unknown.

One copy of the amelogenin gene is located on each of the sex chromosomes (the X and Y chromosomes). The AMELX gene, which is located on the X chromosome, makes almost all of the body's amelogenin. The copy of the amelogenin gene on the Y chromosome, AMELY, makes very little amelogenin and is not needed for enamel formation.

How are changes in the AMELX gene related to health conditions?

amelogenesis imperfecta - caused by mutations in the AMELX gene

At least 15 mutations in the AMELX gene have been identified in people with X-linked forms of amelogenesis imperfecta. (X-linked disorders are caused by mutations in genes on the X chromosome.) Some AMELX mutations lead to the production of an abnormal version of the amelogenin protein that can interfere with the formation and organization of enamel crystals. Other AMELX mutations prevent one copy of the gene from producing any amelogenin protein at all. Enamel cannot form properly without an adequate amount of amelogenin.

Males have a single copy of the X chromosome in each cell. Males who inherit a defective copy of the AMELX gene have very little amelogenin and develop almost no enamel to cover and protect their teeth. Females have two copies of the X chromosome in each cell. Females who inherit one altered copy of the AMELX gene are less severely affected because they have a normal copy of the gene on the other X chromosome to produce amelogenin. Their tooth enamel may have structural defects such as a distinctive pattern of vertical grooves. No symptoms other than abnormal enamel development have been reported in people with AMELX mutations.

Where is the AMELX gene located?

Cytogenetic Location: Xp22.31-p22.1

Molecular Location on the X chromosome: base pairs 11,311,532 to 11,318,880

The AMELX gene is located on the short (p) arm of the X chromosome between positions 22.31 and 22.1.

More precisely, the AMELX gene is located from base pair 11,311,532 to base pair 11,318,880 on the X chromosome.

See How do geneticists indicate the location of a gene? in the Handbook.

Where can I find additional information about AMELX?

You and your healthcare professional may find the following resources about AMELX helpful.

Educational resources - Information pages

School of Dentistry, University of North Carolina at Chapel Hill

Gene Tests - Genetic tests ordered by healthcare professionals

You may also be interested in these resources, which are designed for genetics professionals and researchers.

PubMed - Recent literature

OMIM - Genetic disorder catalog

Research Resources - Tools for researchers (4 links)

What other names do people use for the AMELX gene or gene products?

AIH1

ALGN

amelogenin (amelogenesis imperfecta 1, X-linked)

AMELX_HUMAN

AMG

AMGL

AMGX

See How are genetic conditions and genes named? in the Handbook.

Where can I find general information about genes?

The Handbook provides basic information about genetics in clear language.

What is DNA?

What is a gene?

How do genes direct the production of proteins?

How can gene mutations affect health and development?

These links provide additional genetics resources that may be useful.

Genetics education

Human Genome Project

Resources for Genetic Researchers

What glossary definitions help with understanding AMELX?

amelogenesis ; bone marrow ; cell ; chromosome ; enamel ; gene ; hypoplasia ; mineral ; mutation ; protein ; sex chromosomes ; symptom ; tissue

You may find definitions for these and many other terms in the Genetics Home Reference Glossary.

See also Understanding Medical Terminology.

References (10 links)

출처: http://ghr.nlm.nih.gov/gene/AMELX

Entrez Gene summary for ZFX:

This gene on the X chromosome is structurally similar to a related gene on the Y chromosome. It encodes a member of the krueppel C2H2-type zinc-finger protein family. The full-length protein contains an acidic transcriptional activation domain (AD), a nuclear localization sequence (NLS) and a DNA binding domain (DBD) consisting of 13 C2H2-type zinc fingers. Studies in mouse embryonic and adult hematopoietic stem cells showed that this gene was required as a transcriptional regulator for self-renewal of both stem cell types, but it was dispensable for growth and differentiation of their progeny. Multiple alternatively spliced transcript variants encoding different isoforms have been identified, but the full-length nature of some variants has not been determined. (provided by RefSeq, May 2010)

출처: http://www.genecards.org/cgi-bin/carddisp.pl?gene=ZFX

Turner syndrome

On this page:

Description

Genetic changes

Inheritance

Diagnosis

Additional information

Other names

Glossary definitions

Reviewed January 2012

What is Turner syndrome?

Turner syndrome is a chromosomal condition that affects development in females. The most common feature of Turner syndrome is short stature, which becomes evident by about age 5. An early loss of ovarian function (ovarian hypofunction or premature ovarian failure) is also very common. The ovaries develop normally at first, but egg cells (oocytes) usually die prematurely and most ovarian tissue degenerates before birth. Many affected girls do not undergo puberty unless they receive hormone therapy, and most are unable to conceive (infertile). A small percentage of females with Turner syndrome retain normal ovarian function through young adulthood.

About 30 percent of females with Turner syndrome have extra folds of skin on the neck (webbed neck), a low hairline at the back of the neck, puffiness or swelling (lymphedema) of the hands and feet, skeletal abnormalities, or kidney problems. One third to one half of individuals with Turner syndrome are born with a heart defect, such as a narrowing of the large artery leaving the heart (coarctation of the aorta) or abnormalities of the valve that connects the aorta with the heart (the aortic valve). Complications associated with these heart defects can be life-threatening.

Most girls and women with Turner syndrome have normal intelligence. Developmental delays, nonverbal learning disabilities, and behavioral problems are possible, although these characteristics vary among affected individuals.

How common is Turner syndrome?

This condition occurs in about 1 in 2,500 newborn girls worldwide, but it is much more common among pregnancies that do not survive to term (miscarriages and stillbirths).

What are the genetic changes related to Turner syndrome?

Turner syndrome is related to the X chromosome, which is one of the two sex chromosomes. People typically have two sex chromosomes in each cell: females have two X chromosomes, while males have one X chromosome and one Y chromosome. Turner syndrome results when one normal X chromosome is present in a female's cells and the other sex chromosome is missing or structurally altered. The missing genetic material affects development before and after birth.

About half of individuals with Turner syndrome have monosomy X, which means each cell in the individual's body has only one copy of the X chromosome instead of the usual two sex chromosomes. Turner syndrome can also occur if one of the sex chromosomes is partially missing or rearranged rather than completely absent. Some women with Turner syndrome have a chromosomal change in only some of their cells, which is known as mosaicism. Women with Turner syndrome caused by X chromosome mosaicism are said to have mosaic Turner syndrome.

Researchers have not determined which genes on the X chromosome are associated with most of the features of Turner syndrome. They have, however, identified one gene called SHOX that is important for bone development and growth. The loss of one copy of this gene likely causes short stature and skeletal abnormalities in women with Turner syndrome.

Read more about the SHOX gene and the X chromosome.

Can Turner syndrome be inherited?

Most cases of Turner syndrome are not inherited. When this condition results from monosomy X, the chromosomal abnormality occurs as a random event during the formation of reproductive cells (eggs and sperm) in the affected person's parent. An error in cell division called nondisjunction can result in reproductive cells with an abnormal number of chromosomes. For example, an egg or sperm cell may lose a sex chromosome as a result of nondisjunction. If one of these atypical reproductive cells contributes to the genetic makeup of a child, the child will have a single X chromosome in each cell and will be missing the other sex chromosome.

Mosaic Turner syndrome is also not inherited. In an affected individual, it occurs as a random event during cell division in early fetal development. As a result, some of an affected person's cells have the usual two sex chromosomes, and other cells have only one copy of the X chromosome. Other sex chromosome abnormalities are also possible in females with X chromosome mosaicism.

Rarely, Turner syndrome caused by a partial deletion of the X chromosome can be passed from one generation to the next.

Where can I find information about diagnosis or management of Turner syndrome?

These resources address the diagnosis or management of Turner syndrome and may include treatment providers.

Genetic Alliance

MedlinePlus Encyclopedia: Ovarian Hypofunction

MedlinePlus Encyclopedia: Turner Syndrome

You might also find information on the diagnosis or management of Turner syndrome in Educational resources and Patient support.

General information about the diagnosis and management of genetic conditions is available in the Handbook.

To locate a healthcare provider, see How can I find a genetics professional in my area? in the Handbook.

Where can I find additional information about Turner syndrome?

You may find the following resources about Turner syndrome helpful. These materials are written for the general public.

MedlinePlus - Health information (3 links)

Genetic and Rare Diseases Information Center - Information about genetic conditions and rare diseases

Additional NIH Resources - National Institutes of Health (2 links)

Educational resources - Information pages (10 links)

Patient support - For patients and families (5 links)

You may also be interested in these resources, which are designed for healthcare professionals and researchers.

ClinicalTrials.gov - Linking patients to medical research

PubMed - Recent literature

What other names do people use for Turner syndrome?

monosomy X

TS

Turner's syndrome

Ullrich-Turner syndrome

45,X

For more information about naming genetic conditions, see the Genetics Home Reference Condition Naming Guidelines and How are genetic conditions and genes named? in the Handbook.

What if I still have specific questions about Turner syndrome?

Ask the Genetic and Rare Diseases Information Center.

Where can I find general information about genetic conditions?

The Handbook provides basic information about genetics in clear language.

What does it mean if a disorder seems to run in my family?

What is a chromosome?

Can changes in the number of chromosomes affect health and development?

Are chromosomal disorders inherited?

These links provide additional genetics resources that may be useful.

Genetics and health

Resources for Patients and Families

Resources for Health Professionals

What glossary definitions help with understanding Turner syndrome?

aneuploidy ; aorta ; arteries ; atypical ; cell ; cell division ; chromosome ; complication ; deletion ; developmental delay ; dysgenesis ; egg ; gene ; hormone ; hormone therapy ; infertile ; kidney ; learning disability ; lymphedema ; monosomy ; mosaic ; mosaicism ; nondisjunction ; ovarian ; ovary ; puberty ; reproductive cells ; sex chromosomes ; short stature ; sperm ; stature ; syndrome ; tissue

You may find definitions for these and many other terms in the Genetics Home Reference Glossary.

See also Understanding Medical Terminology.

References (10 links)

출처: http://ghr.nlm.nih.gov/condition/turner-syndrome

ㆍ그러나, Xq에 위치하는 XIST 유전자는 불활성화된 X에서만 발현되며, 불활성화를 유지하는 기능을 갖고 있는 것으로 추정된다.

Entrez Gene summary for XIST:

X inactivation is an early developmental process in mammalian females that transcriptionally silences one of the pair

of X chromosomes, thus providing dosage equivalence between males and females. The process is regulated by several

factors, including a region of chromosome X called the X inactivation center (XIC). The XIC comprises several

non-coding and protein-coding genes, and this gene was the first non-coding gene identified within the XIC. This gene

is expressed exclusively from the XIC of the inactive X chromosome, and is essential for the initiation and spread of

X-inactivation. The transcript is a spliced RNA. Alternatively spliced transcript variants have been identified, but

their full length sequences have not been determined. Mutations in the XIST promoter cause familial skewed X

inactivation. (provided by RefSeq, Apr 2012

출처: http://www.genecards.org/cgi-bin/carddisp.pl?gene=XIST

Models for Xist spreading along the chromosome in cis. Xist RNA (red) and protein factors postulated to bind Xist (orange) are shown. (A) Xist spreading along the chromosome by means of ‘way stations’ or ‘boosters’. (B) Xist spreading based on a cooperative binding mechanism. Xist spreads in cis from its transcription site, where the high RNA concentration is predicted to nucleate chromatin attachment. (C) Schematic representation of the Xi territory with Xist spreading inward from the Xic to the centre of the chromosome territory. LINEs, long interspersed elements; Xic, X-inactivation centre.

출처: http://www.nature.com/embor/journal/v8/n1/fig_tab/7400871_F3.html

ㆍ여성에서 비정상적인 X가 우선적으로 불활성화 되며, 반대로 X-autosome의 전좌가 일어난 경우에는 정상적인 X가 우선적으로 불활성화 된다. 그렇지 않으면, Xq13의 불활성화 중심으로부터 불활성화가 상염색체(autosome)로 퍼질 것이다.

ㆍ불활성 X는 세포 간기에도 응축되어 있어서 관찰이 되며, 이것을 Barr body 라고 한다.

ㆍ세포가 두개 이상의 X 염색체를 갖고 있으면 하나를 제외한 나머지 X들은 불활성화 된다.

ㆍ불활성 X에 있는 house-keeping type 유전자의 CpG island가  hypermethylation 되어 있고, 활성 X의 house-keeping type 유전자는 hypomethylation 되어 있다.

Housekeeping gene

Definition

noun, plural: housekeeping genes

Any of the genes that are constitutively expressed at a relatively constant level across many or all known conditions.

Supplement

Housekeeping genes are those genes that are always expressed because they code for proteins that are constantly required by the cell, hence, they are essential to a cell and always present under any conditions. It is assumed that their expression is unaffected by experimental conditions. The proteins they code are generally involved in the basic functions necessary for the sustenance or maintenance of the cell. Examples of housekeeping genes include actin, GAPDH and ubiquitin.

Compare: luxury gene.
See also: genetic expression, transcription.

출처: http://www.biology-online.org/dictionary/Housekeeping_genes

Origin of CpG (CG) islands

The CG island is a short stretch of DNA in which the frequency of the CG sequence is higher than other regions.  It is also called the CpG island, where "p" simply indicates that "C" and "G" are connected by a phosphodiester bond.

CpG islands are often located around the promoters of housekeeping genes (which are essential for general cell functions) or other genes frequently expressed in a cell.  At these locations, the CG sequence is not methylated.  By contrast, the CG sequences in inactive genes are usually methylated to suppress their expression.  The methylated cytosine may be converted to thymine by accidental deamination.  Unlike the cytosine to uracil mutation which is efficiently repaired, the cytosine to thymine mutation can be corrected only by the mismatch repair which is very inefficient.  Hence, over evolutionary time scales, the methylated CG sequence will be converted to the TG sequence.  This explains the deficiency of the CG sequence in inactive genes.

Inheritance of DNA methylation pattern

Any type of cells have their own methylation pattern so that a unique set of proteins may be expressed to perform functions specific for this cell type.  Thus, during cell division, the methylation pattern should also pass over to the daughter cell.  This is achieved by the enzyme, DNA methyltransferase, which can methylate only the CG sequence paired with methylated CG.

Figure 7-F-2.  Inheritance of the DNA methylation pattern.  The DNA methyltransferase can methylate only the CG sequence paired with methylated CG.  The CG sequence not paired with methylated CG will not be methylated.  Hence,  the original pattern can be maintained after DNA replication.

출처: http://www.web-books.com/MoBio/Free/Ch7F2.htm

ㆍ그 외의 다른 methylation site 들에 있어서는 활성 X의 경우가 hypermethylation 되어 있다는 증거가 있다. methylation 에 의한 유전자의 발현 조절 기작은 잘 모르고 있다.

ㆍ여성은 부계 X가 활성이 있는 세포와 모계 X 가 활성이 있는 세포가 섞여 있다. 이들 세포의 비율은 여성 마다 다르다. 이러한 이유 때문에 X-linked mutant 보인자인 여성의 경우 그 mutant 형질이 군데군데 나타날 수 있다.

Figure 5.12 Diagram of X inactivation

Figure 5.13 Barr body

․X 염색체는 1-10%의 neutrophil에서 drumstick으로 관찰됨

Figure 5.14 Neutrophil drumstick

6. 성 결정과 분화

ㆍ남성결정은 testes-determining factor 유전자에 의해 결정된다. 이 것은 Y 염색체의 짧은 팔에 위치하고 있다. 이 지역이 없으면 생식선이 난소로 되고, 여성으로 분화한다.

ㆍ이 지역이 있으면 정소가 만들어 지는데 정소는 두 가지 호르몬을 생산한다. 세정관의 Sertoli cell 은 Mullerian duct inhibitor를 분비하고, 이것은 원시자궁과 나팔관의 퇴행을 초래한다. 정소의 간 세포들은 testosterone을 분비하고 이것은 Wolffian duct를 자극하여 부정소와 저정낭으로 분화시키고, 외부생식기의 성장을 유도한다.

1: Testicular septa
2: Convoluted seminiferous tubules
3: Testicular lobules
4: Straight seminiferous tubules
5: Efferent ductules
6: Rete testis

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

출처: http://sciortinoycyoulton.blogspot.com/2010/06/seminiferous-tubules.html

Mullerian Ducts

Definition: A pair of ducts near the WOLFFIAN DUCTS in a developing embryo. In the male embryo, they degenerate with the appearance of testicular ANTI-MULLERIAN HORMONE. In the absence of anti-mullerian hormone, mullerian ducts give rise to the female reproductive tract, including the OVIDUCTS; UTERUS; CERVIX; and VAGINA.

출처: http://www.reference.md/files/D009/mD009095.html

Wolffian Ducts

Definition: A pair of excretory ducts of the middle kidneys (MESONEPHROI) of an embryo, also called mesonephric ducts. In higher vertebrates, Wolffian ducts persist in the male forming VAS DEFERENS, but atrophy into vestigial structures in the female.

출처: http://www.reference.md/search.html?w=WOLFFIAN%20DUCTS&m=x

ㆍSRY gene이 TDF 유전자인 것처럼 보인다. 이 유전자는 미분화 생식선에서 발생 특정시기에 발현되고 암쥐 preembryo에 넣으면 성이 바뀐다.

TDF gene

Definition

noun

An abbreviation for testis-determining factor gene, a gene that codes for testis-determining factor in certain animals.

Supplement

Since the presence of Y chromosome in humans indicates maleness, scientists thought that the gene responsible for the determination of maleness in humans must have been located in the Y chromosome. Later, the SRY gene was found. Scientists then believed that this is the testis-determining factor gene since it was found to trigger the pathway that leads to the development of embryo to become male. However, they also pointed out that this gene is not the only gene responsible for sexual development and determination.

출처: http://www.biology-online.org/dictionary/TDF_gene

7. Genomic imprinting

ㆍ상염색체에 있는 두 대립인자는 둘다 활성이 있거나 아니면 둘 다 불활성이다. 그러나, 몇몇 대립인자의 경우에는 두 대립인자 중 어느 하나만 활성이 있고, 불활성화 되는 대립인자는 양친 중 어느 쪽에서 받았느냐는 데에 달려 있다.

ㆍ11p에 있는 insulin-like growth factor 2 의 경우 부계에서 받은 유전자만이 활성이 있다.

IGF2

On this page:

Name

Normal function

Genetic changes

Gene location

Additional information

Other names

About genes

Glossary definitions

Reviewed April 2008

What is the official name of the IGF2 gene?

The official name of this gene is “insulin-like growth factor 2 (somatomedin A).”

IGF2 is the gene's official symbol. The IGF2 gene is also known by other names, listed below.

Read more about gene names and symbols on the About page.

What is the normal function of the IGF2 gene?

The IGF2 gene provides instructions for making a protein called insulin-like growth factor 2. This protein plays an essential role in growth and development before birth. Studies suggest that insulin-like growth factor 2 promotes the growth and division (proliferation) of cells in many different tissues. Although the IGF2 gene is highly active during fetal development, it is much less active in the adult body.

People inherit one copy of most genes from their mother and one copy from their father. Both copies are typically active, or "turned on," in cells. For the IGF2 gene, however, the copy that is inherited from a person's father is the only active copy in most parts of the body. This sort of parent-specific difference in gene activation is caused by a phenomenon called genomic imprinting.

IGF2 is part of a cluster of genes on the short (p) arm of chromosome 11 that undergo genomic imprinting. Another gene in this cluster, H19, is also involved in growth and development. A nearby region of DNA known as imprinting center 1 (ICR1) or the H19 differentially methylated region (H19 DMR) controls the parent-specific genomic imprinting of both the H19 and IGF2 genes.

How are changes in the IGF2 gene related to health conditions?

Beckwith-Wiedemann syndrome - associated with the IGF2 gene

Beckwith-Wiedemann syndrome often results from changes in a process called methylation that affects the ICR1 region. In genes that undergo genomic imprinting, the parent of origin is often marked, or "stamped," on the gene during the formation of egg and sperm cells. This stamping process, called methylation, is a chemical reaction that attaches small molecules called methyl groups to certain segments of DNA.

In some people with Beckwith-Wiedemann syndrome, the ICR1 region has too many methyl groups attached (hypermethylation). Because the ICR1 region controls the genomic imprinting of the H19 and IGF2 genes, this abnormality disrupts the regulation of both genes. Specifically, hypermethylation of the ICR1 region leads to a loss of H19 gene activity and increased activity of the IGF2 gene in many tissues. A loss of H19 gene activity, which normally restrains growth, and an increase in IGF2 gene activity, which promotes growth, together lead to overgrowth and an increased risk of tumors in people with Beckwith-Wiedemann syndrome.

In a few cases, Beckwith-Wiedemann syndrome has been caused by deletions of a small amount of DNA from the ICR1 region. Like abnormal methylation, these deletions disrupt the activity of the H19 and IGF2 genes.

cancers - associated with the IGF2 gene

Increased activity of the IGF2 gene has been associated with many types of cancer. Normally, the IGF2 gene undergoes genomic imprinting and only the copy inherited from a person's father is active. In some cancers, however, both the paternal and the maternal copies of the gene are active, increasing the amount of insulin-like growth factor 2 that cells can produce. This phenomenon is known as loss of imprinting (LOI). An increased amount of insulin-like growth factor 2 may stimulate the growth of tumor cells and prevent damaged cells from being destroyed.

Loss of imprinting of the IGF2 gene has been identified in several types of cancer known as embryonal tumors. These tumors include a rare form of kidney cancer called Wilms tumor, a cancer of muscle tissue called rhabdomyosarcoma, and a form of liver cancer called hepatoblastoma. Although these tumors commonly occur in people with Beckwith-Wiedemann syndrome, loss of imprinting of the IGF2 gene has also been seen in people with these tumors who do not have Beckwith-Wiedemann syndrome.

Loss of imprinting of the IGF2 gene has also been found in many other types of cancer, including cancer of blood-forming cells (leukemia) and cancers of the breast, prostate, lung, colon, and liver. Researchers suspect that this genetic change may someday be used to help predict a person's risk of developing these forms of cancer.

Russell-Silver syndrome - associated with the IGF2 gene

Changes in methylation of the ICR1 region are also responsible for some cases of Russell-Silver syndrome. The changes are different than those seen in Beckwith-Wiedemann syndrome and have the opposite effect on growth.

In Russell-Silver syndrome, the ICR1 region often has too few methyl groups attached (hypomethylation). Hypomethylation of the ICR1 region leads to a loss of IGF2 gene activity and increased activity of the H19 gene in many tissues. A loss of IGF2 gene activity, which normally promotes growth, and an increase in H19 gene activity, which restrains growth, together lead to poor growth and short stature in people with Russell-Silver syndrome.

other disorders - associated with the IGF2 gene

Normal variations (polymorphisms) in the IGF2 gene may be involved in determining adult height and/or weight. These polymorphisms are changes in single protein building blocks (amino acids) used to make insulin-like growth factor 2. Several studies have found associations between polymorphisms in the IGF2 gene and a person's body mass index (a measure of weight in relation to height). Research has also suggested that IGF2 polymorphisms may be a possible risk factor for eating disorders such as anorexia nervosa, bulimia nervosa, and binge eating disorder. Not all studies, however, have supported these associations. Many genetic and environmental factors determine weight and height, and more research is necessary to determine what effect, if any, polymorphisms in the IGF2 gene have on these characteristics.

Where is the IGF2 gene located?

Cytogenetic Location: 11p15.5

Molecular Location on chromosome 11: base pairs 2,150,346 to 2,170,832

The IGF2 gene is located on the short (p) arm of chromosome 11 at position 15.5.

More precisely, the IGF2 gene is located from base pair 2,150,346 to base pair 2,170,832 on chromosome 11.

See How do geneticists indicate the location of a gene? in the Handbook.

Where can I find additional information about IGF2?

You and your healthcare professional may find the following resources about IGF2 helpful.

Educational resources - Information pages (2 links)

Gene Reviews - Clinical summary (2 links)

Gene Tests - Genetic tests ordered by healthcare professionals (2 links)

You may also be interested in these resources, which are designed for genetics professionals and researchers.

PubMed - Recent literature

OMIM - Genetic disorder catalog

Research Resources - Tools for researchers (5 links)

What other names do people use for the IGF2 gene or gene products?

C11orf43

FLJ22066

FLJ44734

IGF-2

IGF2_HUMAN

IGF-II

INSIGF

insulin-like growth factor 2

insulin-like growth factor II

insulin-like growth factor type 2

pp9974

putative insulin-like growth factor II associated protein

somatomedin A

See How are genetic conditions and genes named? in the Handbook.

Where can I find general information about genes?

The Handbook provides basic information about genetics in clear language.

What is DNA?

What is a gene?

How do genes direct the production of proteins?

How can gene mutations affect health and development?

These links provide additional genetics resources that may be useful.

Genetics education

Human Genome Project

Resources for Genetic Researchers

What glossary definitions help with understanding IGF2?

acids ; amino acid ; body mass index ; cancer ; cell ; chromosome ; colon ; deletion ; DNA ; egg ; epigenetic ; gene ; growth factor ; imprinting ; insulin ; kidney ; leukemia ; liver cancer ; maternal ; methyl ; methylation ; molecule ; oncogene ; polymorphism ; proliferation ; prostate ; protein ; rhabdomyosarcoma ; risk factors ; short stature ; sperm ; stature ; syndrome ; tissue ; tumor ; Wilms tumor

You may find definitions for these and many other terms in the Genetics Home Reference Glossary.

See also Understanding Medical Terminology.

References (10 links)

출처: http://ghr.nlm.nih.gov/gene/IGF2

참고사항

H19 (gene)

H19 is a gene for a long noncoding RNA, found in humans and elsewhere. This gene seems to have a role in some forms of cancer. The H19 gene is also known as ASM, ASM1 and BWS, among others.[1]

ASM stands for Adult Skeletal Muscle, and BWS stands for Beckwith-Wiedemann syndrome. H19 was first named ASM because of its expression in adult skeletal muscle in the rat.[2] H19 is also known as BWS because aberrant H19 expression can be involved in Beckwith-Wiedemann Syndrome, as well as Silver-Russell syndrome.[3] The H19 gene is expressed exclusively on one parental allele in a phenomenon known as imprinting.[4] H19 is only transcribed from the maternally inherited allele; the paternal H19 allele is not expressed.[5]

Contents

1 Gene characterization

2 RNA product

3 Expression timeline

4 Epigenetics

5 Replication

6 As an oncogene

6.1 As an oncofetal RNA gene

7 Role in cancer

7.1 Genome instability

7.2 Adrenocortical neoplasms

7.3 Choriocarcinomas

7.4 Hepatocellular carcinoma

7.5 Bladder cancers

7.6 Endometrial/ovarian cancer

7.7 Breast cancer

7.8 Larynx cancer

8 Participation in signaling pathways

8.1 Upstream effectors – hormonal regulation

8.2 Downstream effects – angiogenesis, metabolism, tissue invasion and migration

9 IGF2

10 Cancer therapy

10.1 Gene therapy

10.2 Drug discovery

10.3 Pharmacogenomics

10.4 Immunotherapy

11 References

12 External links

Gene characterization

The H19 gene contains 3 Sp1 binding sites, however these 3 sites are present in a part of the sequence that has shown no transcriptional activity in deletion assays.[6] As a result, these Sp1 binding sites are not expected to contribute much to the regulation of H19 gene transcription. The H19 gene sequence also contains binding sites for the C/EBP family of transcription factors.[6] One of these C/EBP transcription factor binding sites also contains a CpG site.[6] In vitro methylation of this CpG site on a DNA construct strongly inhibited transcription of the H19 gene.[6]

In cell lines derived from human choriocarcinomas, Kopf et al. found that transcription of H19 was under the simultaneous control of both a 5’ upstream and a 3’ downstream region.[7] Kopf et al. have suggested that this simultaneous and bidirectional regulation of H19 may involve a member of the AP2 transcription factor family.[7]

H19 gene transcription has also been shown to be activated by the presence of the E2F1 transcription factor.[8][9]

RNA product

The H19 gene codes for a 2.3 kb RNA product.[10] It is transcribed by RNA polymerase II, spliced and polyadenylated, but it does not appear to be translated.[11]

After many studies, researchers finally concluded that the end product of the H19 gene is a RNA strand for the following reasons:

The H19 RNA product is evolutionarily conserved at the nucleotide level in humans and rodents[12]

There is no known open reading frame; the H19 mRNA contains stop codons in all 3 reading frames [11]

The cDNA version of the human H19 does not contain the short introns that are characteristic of imprinted genes [12]

Although the RNA sequence was highly conserved evolutionarily, at the amino acid level, there was a complete absence of conservation [12]

Free energy (thermodynamics) analysis of the H19 RNA sequence revealed a multitude of possible secondary RNA structures, including 16 helices and various hairpin loops [12]

In situ hybridization of the H19 RNA revealed that it localizes in a cytoplasmic ribonucleoprotein particle, leading some to suggest that the H19 RNA functions as a riboregulator.[13]

Loss of function and overexpression experiments on H19 have revealed two things:

Loss of H19 is not lethal in mice[14]

Overexpression of H19 is a dominant and lethal mutation[10]

Mice with a loss of H19 function express an overgrowth phenotype similar to babies with BWS.[14] This has led researchers to suggest that perhaps the only function of H19 RNA expression is to regulate the expression of IGF2 (Insulin Growth Factor 2).[14] Overexpression of IGF2 can be responsible for overgrowth, and generally, IGF2 is expressed in the absence of H19. Mouse embryos overexpressing H19 tend to die between embryonic day 14 and birth.[10] Brunkow et al. have suggested two reasons for the lethality of H19 overexpression in embryonic mice:

The overexpression of H19 in tissues where it is normally expressed (e.g., liver and gut) caused its lethal effects[10]

This implies that H19 gene dosage is under strict control in the fetus

The expression of H19 in tissues where it is normally not expressed (e.g., brain) caused its lethal effects[10]

Expression timeline

In the early placentae (6–8 weeks gestation), both parental H19 alleles (maternal and paternal) are expressed.[15][16]

After 10 weeks gestation and in full term placentae, there is exclusive expression of H19 from the maternal chromosome.[15][16] In the embryo, maternal expression of H19 is present in endodermal and mesodermal tissues.[10] The regulated expression of H19, from biallelic to monoallelic, throughout embryonic development suggests that regulation is essential for the growth of embryonic and extraembryonic tissues.[15] Immediately after birth, H19 expression is downregulated in all tissues except for skeletal muscle.[10]

Studies by Tanos et al. suggest that the accumulation of H19 RNA in skeletal muscle cells is solely due to the stabilization of that RNA in the muscle cells during differentiation.[17]

In females, H19 is expressed postnatally during puberty and pregnancy in the mammary glands, and in the uterus during pregnancy.[18]

Epigenetics

Genomic imprinting is surmised to have arisen due to the conflicting interests of maternal and paternal genes within a pregnancy.[19]

Within a pregnancy, the father wants the mother to devote as much of her resources as possible towards the growth (benefit) of his offspring.[19] However, within the same pregnancy, the mother wants to conserve as much of her resources as possible towards future births without compromising the health of the child(ren) she is currently carrying.[19]

H19 contains a differentially methylated region that is also an imprinting control region. This imprinting control region is differentially methylated at its CpGs according to parental inheritance. Usually, the paternal copy of H19 is methylated and silent while the maternal copy is hypomethylated or unmethylated and expressed in the offspring cell. Methylation of the H19 promoter is negatively correlated with H19 expression.[20]

As methylation of the promoter reaches 100%, H19 expression from that promoter approaches 0.[20] At the same time as H19 expression decreases, the expression of IGF2, a neighboring gene on chromosome 11, increases.[20]

Cells treated with Azad, a demethylating agent, grow much slower than cells cultured in the absence of Azad.[20] At the same time, H19 expression increases while IGF2 expression decreases in the presence of Azad.[20] The reduction of IGF2 expression could be a reason for the slower growth of cells treated with Azad. As well, in a mouse bladder carcinoma cell line, where transfection of a human H19 DNA construct results in high expression of H19, the methylation of the H19 promoter reduces H19 expression.[16] The paternal H19 allele, which is silent postnatally, shows increasing methylation of CpGs in its promoter with gestation time in the fetus.[16] It appears conclusive that the H19 gene is epigenetically controlled via methylation, where methylation on or near the vicinity of one allele prevents the expression of that allele. As well, based on the results from Banet et al., it appears that functional H19 imprinting occurs during early placenta development.[16]

Replication

A common characteristic of imprinted genes is asynchronous replication during the DNA synthesis phase of the mitotic cycle.[12] The replication of two alleles of the same gene can differ according to which parent the allele originated from.[12] On the human chromosome 11p15, the methylated paternal H19 allele replicates early in the S phase while the hypomethylated maternal allele replicates later.[12] Studies by Bergstrom et al. have determined that the later-replicating maternal H19 allele is CTCF-bound, and that it is this CTCF binding that determines the time of H19 replication.[12]

As an oncogene

Evidence for the identification of H19 as an oncogene:

Overexpression of H19 appears to be important in the development of esophageal and colorectal cancer cells[21]

Cells expressing H19 are able to form bigger colonies in soft agar in anchorage-independent growth assays as compared to the control.[22]

Downregulation of H19 in breast and lung cancer cells decreases their clonogenicity and anchorage-dependent growth[23]

Subcutaneous injection of H19 into mice promoted tumor progression[22]

Tumors formed by injection of bladder carcinoma cells into mice express H19; prior to the injection, these bladder carcinoma cells did not express H19.[24]

Ectopic H19 expression in vivo enhances the tumorigenic potential of carcinoma cells[25]

c-Myc, an oncogene that functions as a regulator of gene transcription, induces H19 expression[23]

Knocking down H19 in hypoxic stress diminishes p57 induction[25]

Evidence against the identification of H19 as an oncogene:

The amount of H19 RNA transfected into breast cancer cells did not affect: cell proliferation, cell cycle timing or anchorage-dependent growth[22]

As an oncofetal RNA gene

Definition of an oncofetal gene:

A gene expressed in tumors arising from tissues that express this gene in fetal life[26]

H19, while possessing oncogenic properties, is best defined as an oncofetal RNA gene because:

The final product of the H19 gene is RNA[26]

H19 is highly expressed prenatally and downregulated postnatally[15]

Postnatally, H19 is expressed at high levels in cancer cells[10]

Role in cancer

Increased H19 expression is found in the following cancers: adrenocortical neoplasms, choriocarcinomas, hepatocellular carcinomas, bladder cancers, ovarian serous epithelial cancers, head and neck carcinomas, endometrial cancer, breast cancer, acute T cell leukemia/lymphoma, Wilms' tumor, testicular germ cell cancer, esophageal cancer and lung cancer.[8][15][16][17][20][27][28][29][30]

Genome instability

Main article: Genome instability

Cellular DNA integrity is often compromised in cancer. Genome instability can refer to the accumulation of extra copies of DNA/chromosomes, chromosomal translocations, chromosomal inversion, chromosome deletions, single stranded breaks in DNA, double stranded breaks in DNA, the intercalation of foreign substances into the DNA double helix, or any abnormal changes in DNA tertiary structure that can cause either the loss of DNA, or the misexpression of genes. Whether or not H19 RNA has any role in destabilizing the genome of a cell is unknown.

Adrenocortical neoplasms

In contrast to most other cancers, adrenocortical neoplasms appear to have decreased expression of H19. To determine a possible cause for the downregulation of H19, Gao et al. studied the methylation of 12 CpG sites in the H19 promoter in normal, hyperplasia, adenoma and carcinoma adrenals. They found that in carcinomas, there was more methylation of CpGs than in normal, hyperplasia and adenoma adrenals.[20] Consequently, normal H19 expression was detectable in normal and hyperplasia adrenals, but in carcinomas and surprisingly, adenomas, there was a lower H19 expression that was coupled with detectable (increased) IGF2 expression.[20]

The presence of IGF2 RNA expression when H19 RNA was downregulated provides further evidence that IGF2 expression is tightly coupled to and dependent on the absence of H19 expression. As well, the loss of H19 in adrenal cancers may be indicative of tumor suppressor activity by H19, leading Gao et al. to suggest that the loss of H19 and subsequent gain of IGF2 may be involved in adrenal cancer induction. Although Gao et al. found that there was not one CpG methylation site that was more important than the others in downregulating H19 expression, they did find that the increase in CpG methylation in adrenal carcinomas followed the pattern of methylation of the normal, hyperplasia and adenoma adrenals. The mean percent methylation of H19 CpGs peaked at sites 9 and 10 in normal, hyperplasia, adenoma and carcinoma adrenals and the lowest mean percent methylation of H19 CpGs dipped at site 7 in normal, hyperplasia, adenoma and carcinoma adrenals.

It is interesting to note that the mean percent methylation of H19 CpGs at sites 13 and 14, after the transcription start site, is insignificant between normal, hyperplasia, adenoma and carcinoma adrenals. This is because methylation of CpGs after the transcription start site is assumed to interfere with RNA polymerase II during transcription. Another point of interest is the significant difference in CpG methylation at site 11 between normal and hyperplasia adrenals. The mean percent CpG methylation at site 11 for hyperplasia and adenoma adrenals is significantly different from that of normal adrenals and carcinoma adrenals, leading Gao et al. to suggest that site 11 is the initial methylated CpG that eventually leads to widespread methylation of the H19 promoter.[20]

Choriocarcinomas

Choriocarcinomas, in contrast to adrenal carcinomas, have upregulated H19 and downregulated IGF2 expression.[15] The upregulated H19 expression, however, came from alleles that were fully methylated.[15] Surgically removed choriocarcinomas from human patients also exhibited a heavily methylated H19 promoter with enhanced H19 expression.[15] This led researchers Arima et al. to suggest that in cases of choriocarcinomas, the H19 promoter was mutated, allowing it to overcome the transcriptional repression of promoter CpG methylation.

Hepatocellular carcinoma

In hepatocellular carcinoma, the expression of H19 and IGF2 usually changes from monoallelic to biallelic.[25] In in vitro studies, culturing hepatocellular carcinoma cell lines in hypoxic condition upregulated H19 expression.[25] Whether or not the loss of imprinting for the H19 promoter is a characteristic of hepatocellular carcinoma is not known, as some cell lines exhibit loss of imprinting while others did not.

Bladder cancers

Bladder mucosa is one of the tissues that express high levels of H19 RNA prenatally.[30] In bladder cancers, H19 is also upregulated and present in most stages.[16] The presence of H19 RNA was strongest in bladder carcinomas (sampled in situ) that tend to progress rapidly to invasive cancer as well as invasive transitional cell carcinomas.[31]

In samples of bladder carcinoma, loss of imprinting at the H19 loci were observed.[24] Verhaugh et al. investigated various polymorphisms in the H19 gene and found that some heterozygous SNP polymorphisms, such as rs2839698 TC, were associated with a decreased risk of developing non-muscle invasive bladder cancer as well as bladder cancer overall; however, this association disappeared for homozygotes (CC).[32]

Endometrial/ovarian cancer

In normal endometrial tissue, there is no H19 expression; however, in endometrial cancer, H19 is expressed.[17] The expression level of H19 RNA in the epithelial cells of the endometrium increases as tissue differentiation is lost in endometrial cancer.[17]

In ovarian cancers, 75% of low malignancy tumors and 65% of invasive ovarian carcinomas are H19 RNA positive.[27]

Breast cancer

Normal breast tissue does not express H19 RNA, except during puberty and pregnancy in the mammary glands.[33]

However, in breast cancer, 72.5% of the breast adenocarcinomas studied by Adriaenssens et al. displayed increased H19 expression when compared to normal breast tissue. Of the tissues with upregulated H19, 92.2% are stromal cells and only 2.9% are epithelial cells.[33] Studies by Berteaux et al. have also found that the overexpression of H19 in breast cancer cells promotes proliferation.[9] The expression of H19 in these cells is also independent of the tumor suppressor protein p53 and the cell cycle marker Ki-67.[33] However, the presence of tumor suppressor protein pRb and transcription factor E2F6 is sufficient to repress H19 expression in breast cancer cells.[9]

In experiments conducted by Doyle et al., it was found that MCF-7, a breast adenomacarcinoma cell line,[34] did not express the H19 gene; however a subline of MCF-7 with a multidrug resistance phenotype, MCF-7/AdrVp, had upregulation of H19.[29] Curiously, mutant revertant MCF-7/AdrVp cells that lost their multidrug resistance and became drug-sensitive also lost H19 expression.[29] Drug-resistant MCF-AdrVp cells do not overexpress P-glycoprotein, a cell membrane efflux pump commonly found in multidrug resistant cells; instead, they overexpress a 95kD membrane glycoprotein p95.[29] p95, or NCA-90, is related to carcinoembryonic antigens, which have been found to reduce drug toxicity by Kawaharata et al..[35][36]

NCI-H1688, a human lung carcinoma cell line that displays multidrug resistance, also overexpress p95 (NCA-90) and H19.[29] No other cell lines with the multidrug resistance phenotype have been found to overexpress p95 (NCA-90) in conjunction with H19.[29]

Larynx cancer

H19 is overexpressed in laryngeal squamous cell carcinomas that relapse as compared to those that do not relapse. In a pilot study aimed at the development of a prognostic classifier for this cancer H19 was the strongest predictor of relapse. It was overexpressed in cancers that later developed local or distant recurrence. Interestingly, its expression did not correlate with the expression of IGF2 and H19 overexpression is unlikely to be a simple consequence of loss of imprinting of the locus containing H19 and IGF2 [37]

Participation in signaling pathways

The exact role of H19 RNA within the cell is currently not known. There are various known substances and conditions that are known to activate H19 transcription and there are various known effects of H19 RNA on cell cycle activity/status, although precisely how H19 RNA exerts these effects is still unknown.

Upstream effectors – hormonal regulation

A previous study conducted by Adriaenssens et al. on H19 correlated an overexpression of H19 with the presence of steroid receptors.[18]

Further studies found that 17-β-estradiol, the dominant form of estrogen, and corticosterone were able to individually stimulate H19 transcription in the uterus, while the presence of progesterone inhibited this effect.[18] Tamoxifen is a competitive binder of the estrogen receptor and is often used in chemotherapy treatment of breast cancer. While 17-β-estradiol alone stimulated H19 transcription in MCF-7 cells, the addition of tamoxifen inhibited H19 transcription, demonstrating that there is a putative role of hormones in H19 transcription.[18]

Downstream effects – angiogenesis, metabolism, tissue invasion and migration

When a cancer bladder cell line, T24P, which does not express H19 was transfected with a DNA construct expressing the H19 gene under the control of the cytomegalovirus promoter, many changes were seen in the resulting cells when compared to both the original T24P cell line and a H19-antisense DNA construct transfected T24P cell line. While there was no difference in proliferation in 10% FCS (normal condition) between the 3 cell lines, when grown in 0.1% FCS (starved serum), the H19-transfected cells maintained their rate of growth while both the control and the antisense H19 transfected cells decreased their rate of proliferation by approximately 50%.[38]

When p57 induction in 0.1% FCS media was measured in the 3 cell lines, both the control and antisense H19 transfected cells had significantly upregulated p57; however, the H19-transfected cells showed a significant downregulation of p57 in 0.1% FCS as compared to 10% FCS.[38] In addition, while the expression of PCNA, required for progression of the cell cycle beyond the S phase, was significantly downregulated in all 3 cell lines, the reduction was approximately 80%-90% in the control and antisense H19 transfected cells and only 30% in the H19 transfected cells.[38]

An examination of the differences in gene expressed between the H19 transfected cells and the antisense H19 transfected cells showed that the following genes were upregulated: uPar, c-src kinase, tyrosine kinase 2 mitogen-activated protein kinase kinase, tyrosine kinase 2, c-jun, JNK1, Janus kinase 1, TNF-a, interleukin-6, heparin-binding growth factor-like growth factor, intracellular adhesion molecule 1, NF-κB, ephrin A4 and ezrin.[38] It is also suggested that angiogenin and FGF18 may be potential transcriptional targets of the H19 RNA.[25] As a result of the functions and signaling pathways that H19 RNA-upregulated genes are involved in, it has been suggested that H19 RNA plays crucial roles in tissue invasion, migration and angiogenesis in tumorigenesis.[38]

Lottin et al. also found that the overexpression of H19 positively regulates post-transcriptionally thioredoxin.[39] Thioredoxin is a protein crucial to the reduction-oxidation reactions involved in metabolism within a cell, and is often found at high levels in cancerous tissues that also overexpress H19 RNA.[39]

IGF2

H19 and IGF2 expression are closely linked, as they are expressed in the same tissues during fetal development, albeit from differing parental alleles.

[14] This coupled expression is only lost in cases of loss of imprinting (inherited CpG methylated) or promoter mutation.[40]

The hypermethylation of the H19 promoter on the paternal allele plays a vital role in allowing the expression of the paternal allele of IGF2.[20] In DNMT-null mice, the paternal allele of IGF2 is also silenced as the paternal H19 promoter is no longer methylated and repressed.[14] A reason for the close coupling of H19 and IGF2 expression may be that they share the same 3’ gene enhancer.[14] When this 3’ enhancer was deleted, researchers Leighton et al. found decreased H19 and IGF2 RNA expressions in the gut, liver and kidney; however, the methylation status of these genes were not affected by the deleted enhancer.[14] Suggestions for why H19 is preferentially activated by the 3’ enhancer instead of IGF2 are that H19 has a stronger promoter than IGF2 and that the H19 gene is physically closer to the 3’ enhancers than the IGF2 gene.[41]

It is of interest to note that mice inheriting a deleted maternal H19 and a deleted paternal IGF2 gene were indistinguishable from wildtype mice in birth weight and postnatal growth.[41] Mice inheriting only a deleted maternal H19 gene, however, displayed somatic overgrowth while mice inheriting only a deleted paternal IGF2 gene displayed somatic undergrowth when compared to wildtype mice.[41] This indicates that the loss of H19 is not lethal, H19 expression governs IGF2 repression, and the overexpression of IGF2 is responsible for the overgrowth phenotype observed in the maternal inheritance of a deleted H19 gene.[41]

Cancer therapy

While the functions of the H19 RNA in the cell are still unclear, its presence in the many types of carcinoma cells suggest that it can be used as a tumor marker for initial diagnosis, cancer recurrence and malignant potential.[17][31][42]

Gene therapy

The activation of the H19 promoter in cancerous cells (and its silence in normal tissues) has led to the suggestion of using the H19 promoter in gene therapy to drive the expression of cytotoxic genes in tumorigenic cells.[16] Gene therapy trials utilizing the H19 promoter to drive the expression of cytotoxic genes are currently being tested on mice.[16]

Drug discovery

A plasmid composed of the H19 gene regulatory sequences that drive the expression of the 'A' strand of Diphtheria Toxin (DT-A), is undergoing clinical testing as a treatment for superficial bladder cancer,[43] ovarian cancer[44] and pancreatic cancer.[45] The plasmid, designated BC-819 (or DTA-H19), embodies a targeted therapy approach, in that the plasmid enters all dividing cells, but the DT-A expression is triggered by the presence of H19 transcription factors found only in tumor cells, thus destroying the tumor without affecting normal cells.

In a double-center, dose escalation Phase I/IIa clinical trial of BC-819 as a treatment for superficial bladder cancer,[46] no severe adverse events related to the plasmid were detected, and tumor responses were observed in more than 70% of patients, including those with a still not-optimized therapeutic dose and regimen.

BC-819 was previously tested in human compassionate use for the treatment of superficial bladder cancer, ovarian cancer and metastatic liver cancer. The bladder cancer patient, who was a candidate for radical cystectomy when he was treated in 2004, reported no cancer recurrence and no side effects.[46] The ovarian cancer patient experienced a 50% decline in the amount of the ovarian cancer marker protein CA-125 in her blood as well as a significant decrease in the number of cancerous cells in her ascitic fluid. The patient suffering from metastatic liver cancer was treated with direct injection of BC-819 into the tumor, with considerable tumor necrosis observed.

Pharmacogenomics

While the expression profile of H19 in most cancer types is known, the role of H19 RNA in influencing cancer cell response to drug treatment is still unknown. However, recent studies have discovered the expression of thioredoxin and p95 (NCA-90) in cancer cells when H19 RNA is present in high quantities.[29][39] This knowledge can lead to a more personalized cancer treatment plan; for example, the expression of p95 in a H19-overexpressing cancer cell may indicate higher tolerance of drug toxicity, so cancer treatment for an individual with high levels of H19 (and p95) may focus more on radiotherapy or immunotherapy instead of chemotherapy.

Immunotherapy

It is not currently known if H19 expression can be used to induce an anti-cancer response in immune cells.

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^ a b c d Leighton PA, Ingram RS, Eggenschwiler J, Efstratiadis A, Tilghman SM (May 1995). "Disruption of imprinting caused by deletion of the H19 gene region in mice". Nature 375 (6526): 34–9. doi:10.1038/375034a0. PMID 7536897.

^ Ariel I, Sughayer M, Fellig Y, Pizov G, Ayesh S, Podeh D, Libdeh BA, Levy C, Birman T, Tykocinski ML, de Groot N, Hochberg A (December 2000). "The imprinted H19 gene is a marker of early recurrence in human bladder carcinoma". MP, Mol. Pathol. 53 (6): 320–3. doi:10.1136/mp.53.6.320. PMC 1186987. PMID 11193051. http://mp.bmj.com/cgi/content/abstract/53/6/320.

^ "Phase 2b, Trial of Intravesical DTA-H19/PEI in Patients With Intermediate-Risk Superficial Bladder Cancer". ClinicalTrials.gov. U.S. National Institutes of Health. 2009-08-31. http://clinicaltrials.gov/ct2/show/NCT00595088. Retrieved 2010-01-14.

^ "Phase 1/2a Study of DTA-H19 in Advanced Stage Ovarian Cancer With Symptomatic Ascites". ClinicalTrials.gov. U.S. National Institutes of Health. 2009-12-03. http://clinicaltrials.gov/ct2/show/NCT00826150. Retrieved 2010-01-14.

^ "Phase 1/2a DTA-H19 in Patients With Unresentable Pancreatic Cancer". ClinicalTrials.gov. U.S. National Institutes of Health. 2009-11-09. http://clinicaltrials.gov/ct2/show/NCT00711997. Retrieved 2010-01-14.

^ a b Sidi AA, Ohana P, Benjamin S, Shalev M, Ransom JH, Lamm D, Hochberg A and Leibovitch I (12 2008). "Phase I/II Marker Lesion Study of Intravesical BC-819 DNA Plasmid in H19 Over Expressing Superficial Bladder Cancer Refractory to Bacillus Calmette-Guerin". The Journal of Urology 180 (6): 2379–2383. doi:10.1016/j.juro.2008.08.006. ISSN 0022-5347. PMID 18950807.

출처: http://en.wikipedia.org/wiki/H19_(gene)

ㆍ이러한 각인은 생식세포형성과정에서 생기며, 유전자에 인접한 특정부위에 methylation의 차이가 관여하는 것으로 보인다.

ㆍimprinting의 이유는 모르지만, 이러한 imprinting의 결과 특정 염색체 질환에 대한 표현형이 그 염색체의 parental origin에 의존한다. 예를 들면, 모계 15번 염색체의 긴팔 부위가 결손 되면, 정신지체가 있는 Angelman syndrome이 발생하고, 부계 15번 염색체의 동일부위가 결손 되면, 좀 다른 증상을 갖는 Prader-Willi syndrome이 생긴다.

Angelman syndrome

On this page:

Description

Genetic changes

Inheritance

Diagnosis

Additional information

Other names

Glossary definitions

Reviewed October 2011

What is Angelman syndrome?

Angelman syndrome is a complex genetic disorder that primarily affects the nervous system. Characteristic features of this condition include delayed development, intellectual disability, severe speech impairment, and problems with movement and balance (ataxia). Most affected children also have recurrent seizures (epilepsy) and a small head size (microcephaly). Delayed development becomes noticeable by the age of 6 to 12 months, and other common signs and symptoms usually appear in early childhood.

Children with Angelman syndrome typically have a happy, excitable demeanor with frequent smiling, laughter, and hand-flapping movements. Hyperactivity, a short attention span, and a fascination with water are common. Most affected children also have difficulty sleeping and need less sleep than usual.

With age, people with Angelman syndrome become less excitable, and the sleeping problems tend to improve. However, affected individuals continue to have intellectual disability, severe speech impairment, and seizures throughout their lives. Adults with Angelman syndrome have distinctive facial features that may be described as "coarse." Other common features include unusually fair skin with light-colored hair and an abnormal side-to-side curvature of the spine (scoliosis). The life expectancy of people with this condition appears to be nearly normal.

How common is Angelman syndrome?

Angelman syndrome affects an estimated 1 in 12,000 to 20,000 people.

What are the genetic changes related to Angelman syndrome?

Many of the characteristic features of Angelman syndrome result from the loss of function of a gene called UBE3A. People normally inherit one copy of the UBE3A gene from each parent. Both copies of this gene are turned on (active) in many of the body's tissues. In certain areas of the brain, however, only the copy inherited from a person's mother (the maternal copy) is active. This parent-specific gene activation is caused by a phenomenon called genomic imprinting. If the maternal copy of the UBE3A gene is lost because of a chromosomal change or a gene mutation, a person will have no active copies of the gene in some parts of the brain.

Several different genetic mechanisms can inactivate or delete the maternal copy of the UBE3A gene. Most cases of Angelman syndrome (about 70 percent) occur when a segment of the maternal chromosome 15 containing this gene is deleted. In other cases (about 11 percent), Angelman syndrome is caused by a mutation in the maternal copy of the UBE3A gene.

In a small percentage of cases, Angelman syndrome results when a person inherits two copies of chromosome 15 from his or her father (paternal copies) instead of one copy from each parent. This phenomenon is called paternal uniparental disomy. Rarely, Angelman syndrome can also be caused by a chromosomal rearrangement called a translocation, or by a mutation or other defect in the region of DNA that controls activation of the UBE3A gene. These genetic changes can abnormally turn off (inactivate) UBE3A or other genes on the maternal copy of chromosome 15.

The causes of Angelman syndrome are unknown in 10 to 15 percent of affected individuals. Changes involving other genes or chromosomes may be responsible for the disorder in these cases.

In some people who have Angelman syndrome, the loss of a gene called OCA2 is associated with light-colored hair and fair skin. The OCA2 gene is located on the segment of chromosome 15 that is often deleted in people with this disorder. However, loss of the OCA2 gene does not cause the other signs and symptoms of Angelman syndrome. The protein produced from this gene helps determine the coloring (pigmentation) of the skin, hair, and eyes.

Read more about the OCA2 and UBE3A genes and chromosome 15.

Can Angelman syndrome be inherited?

Most cases of Angelman syndrome are not inherited, particularly those caused by a deletion in the maternal chromosome 15 or by paternal uniparental disomy. These genetic changes occur as random events during the formation of reproductive cells (eggs and sperm) or in early embryonic development. Affected people typically have no history of the disorder in their family.

Rarely, a genetic change responsible for Angelman syndrome can be inherited. For example, it is possible for a mutation in the UBE3A gene or in the nearby region of DNA that controls gene activation to be passed from one generation to the next.

Where can I find information about diagnosis or management of Angelman syndrome?

These resources address the diagnosis or management of Angelman syndrome and may include treatment providers.

Gene Review: Angelman Syndrome

Gene Tests: Angelman Syndrome

MedlinePlus Encyclopedia: Speech Disorders

You might also find information on the diagnosis or management of Angelman syndrome in Educational resources and Patient support.

General information about the diagnosis and management of genetic conditions is available in the Handbook.

To locate a healthcare provider, see How can I find a genetics professional in my area? in the Handbook.

Where can I find additional information about Angelman syndrome?

You may find the following resources about Angelman syndrome helpful. These materials are written for the general public.

MedlinePlus - Health information (3 links)

Genetic and Rare Diseases Information Center - Information about genetic conditions and rare diseases

Additional NIH Resources - National Institutes of Health

National Institute of Neurological Disorders and Stroke

Educational resources - Information pages (4 links)

Patient support - For patients and families (7 links)

You may also be interested in these resources, which are designed for healthcare professionals and researchers.

Gene Reviews - Clinical summary

Gene Tests - Genetic tests ordered by healthcare professionals

ClinicalTrials.gov - Linking patients to medical research

PubMed - Recent literature

OMIM - Genetic disorder catalog

What other names do people use for Angelman syndrome?

AS

For more information about naming genetic conditions, see the Genetics Home Reference Condition Naming Guidelines and How are genetic conditions and genes named? in the Handbook.

What if I still have specific questions about Angelman syndrome?

Ask the Genetic and Rare Diseases Information Center.

Where can I find general information about genetic conditions?

The Handbook provides basic information about genetics in clear language.

What does it mean if a disorder seems to run in my family?

What is a chromosome?

Can changes in the number of chromosomes affect health and development?

Are chromosomal disorders inherited?

What are genomic imprinting and uniparental disomy?

These links provide additional genetics resources that may be useful.

Genetics and health

Resources for Patients and Families

Resources for Health Professionals

What glossary definitions help with understanding Angelman syndrome?

ataxia ; cell ; chromosome ; deletion ; DNA ; egg ; embryonic ; gene ; hyperactivity ; imprinting ; maternal ; microcephaly ; mutation ; nervous system ; pigmentation ; protein ; rearrangement ; reproductive cells ; scoliosis ; seizure ; sign ; spectrum ; sperm ; symptom ; syndrome ; tissue ; translocation ; uniparental disomy

You may find definitions for these and many other terms in the Genetics Home Reference Glossary.

See also Understanding Medical Terminology.

References (11 links)

출처: http://ghr.nlm.nih.gov/condition/angelman-syndrome

Prader-Willi syndrome

On this page:

Description

Genetic changes

Inheritance

Diagnosis

Additional information

Other names

Glossary definitions

Reviewed October 2011

What is Prader-Willi syndrome?

Prader-Willi syndrome is a complex genetic condition that affects many parts of the body. In infancy, this condition is characterized by weak muscle tone (hypotonia), feeding difficulties, poor growth, and delayed development. Beginning in childhood, affected individuals develop an insatiable appetite, which leads to chronic overeating (hyperphagia) and obesity. Some people with Prader-Willi syndrome, particularly those with obesity, also develop type 2 diabetes mellitus (the most common form of diabetes).

People with Prader-Willi syndrome typically have mild to moderate intellectual impairment and learning disabilities. Behavioral problems are common, including temper outbursts, stubbornness, and compulsive behavior such as picking at the skin. Many affected individuals also have sleep abnormalities. Additional features of this condition include distinctive facial features (such as a narrow forehead, almond-shaped eyes, and a triangular mouth), short stature, and small hands and feet. Some people with Prader-Willi syndrome have unusually fair skin and light-colored hair. Both affected males and affected females have underdeveloped genitals. Puberty is delayed or incomplete, and most affected individuals are unable to have children (infertile).

How common is Prader-Willi syndrome?

Prader-Willi syndrome affects an estimated 1 in 10,000 to 30,000 people worldwide.

What are the genetic changes related to Prader-Willi syndrome?

Prader-Willi syndrome is caused by the loss of function of genes in a particular region of chromosome 15. People normally inherit one copy of this chromosome from each parent. Some genes are turned on (active) only on the copy that is inherited from a person's father (the paternal copy). This parent-specific gene activation is caused by a phenomenon called genomic imprinting.

Most cases of Prader-Willi syndrome (about 70 percent) occur when a segment of the paternal chromosome 15 is deleted in each cell. People with this chromosomal change are missing certain critical genes in this region because the genes on the paternal copy have been deleted, and the genes on the maternal copy are turned off (inactive). In another 25 percent of cases, a person with Prader-Willi syndrome has two copies of chromosome 15 inherited from his or her mother (maternal copies) instead of one copy from each parent. This phenomenon is called maternal uniparental disomy. Rarely, Prader-Willi syndrome can also be caused by a chromosomal rearrangement called a translocation, or by a mutation or other defect that abnormally turns off (inactivates) genes on the paternal chromosome 15.

It appears likely that the characteristic features of Prader-Willi syndrome result from the loss of function of several genes on chromosome 15. Among these are genes that provide instructions for making molecules called small nucleolar RNAs (snoRNAs). These molecules have a variety of functions, including helping to regulate other types of RNA molecules. (RNA molecules play essential roles in producing proteins and in other cell activities.) Studies suggest that the loss of a particular group of snoRNA genes, known as the SNORD116 cluster, may play a major role in causing the signs and symptoms of Prader-Willi syndrome. However, it is unknown how a missing SNORD116 cluster could contribute to intellectual disability, behavioral problems, and the physical features of the disorder.

In some people with Prader-Willi syndrome, the loss of a gene called OCA2 is associated with unusually fair skin and light-colored hair. The OCA2 gene is located on the segment of chromosome 15 that is often deleted in people with this disorder. However, loss of the OCA2 gene does not cause the other signs and symptoms of Prader-Willi syndrome. The protein produced from this gene helps determine the coloring (pigmentation) of the skin, hair, and eyes.

Read more about the OCA2 gene and chromosome 15.

Can Prader-Willi syndrome be inherited?

Most cases of Prader-Willi syndrome are not inherited, particularly those caused by a deletion in the paternal chromosome 15 or by maternal uniparental disomy. These genetic changes occur as random events during the formation of reproductive cells (eggs and sperm) or in early embryonic development. Affected people typically have no history of the disorder in their family.

Rarely, a genetic change responsible for Prader-Willi syndrome can be inherited. For example, it is possible for a genetic change that abnormally inactivates genes on the paternal chromosome 15 to be passed from one generation to the next.

Where can I find information about diagnosis or management of Prader-Willi syndrome?

These resources address the diagnosis or management of Prader-Willi syndrome and may include treatment providers.

Gene Review: Prader-Willi Syndrome

Gene Tests: Prader-Willi Syndrome

MedlinePlus Encyclopedia: Hypotonia

MedlinePlus Encyclopedia: Prader-Willi syndrome

You might also find information on the diagnosis or management of Prader-Willi syndrome in Educational resources and Patient support.

General information about the diagnosis and management of genetic conditions is available in the Handbook.

To locate a healthcare provider, see How can I find a genetics professional in my area? in the Handbook.

Where can I find additional information about Prader-Willi syndrome?

You may find the following resources about Prader-Willi syndrome helpful. These materials are written for the general public.

MedlinePlus - Health information (3 links)

Genetic and Rare Diseases Information Center - Information about genetic conditions and rare diseases

Additional NIH Resources - National Institutes of Health

Eunice Kennedy Shriver National Institute of Child Health and Human Development

Educational resources - Information pages (3 links)

Patient support - For patients and families (7 links)

You may also be interested in these resources, which are designed for healthcare professionals and researchers.

Gene Reviews - Clinical summary

Gene Tests - Genetic tests ordered by healthcare professionals

ClinicalTrials.gov - Linking patients to medical research

PubMed - Recent literature

OMIM - Genetic disorder catalog

What other names do people use for Prader-Willi syndrome?

Prader-Labhart-Willi syndrome

PWS

Willi-Prader syndrome

For more information about naming genetic conditions, see the Genetics Home Reference Condition Naming Guidelines and How are genetic conditions and genes named? in the Handbook.

What if I still have specific questions about Prader-Willi syndrome?

Ask the Genetic and Rare Diseases Information Center.

Where can I find general information about genetic conditions?

The Handbook provides basic information about genetics in clear language.

What does it mean if a disorder seems to run in my family?

What is a chromosome?

Can changes in the number of chromosomes affect health and development?

Are chromosomal disorders inherited?

What are genomic imprinting and uniparental disomy?

These links provide additional genetics resources that may be useful.

Genetics and health

Resources for Patients and Families

Resources for Health Professionals

What glossary definitions help with understanding Prader-Willi syndrome?

cell ; chromosome ; chronic ; contiguous ; contiguous gene syndrome ; deletion ; diabetes ; diabetes mellitus ; egg ; embryonic ; gene ; genitals ; hyperphagia ; hypogonadism ; hypotonia ; imprinting ; infertile ; learning disability ; maternal ; molecule ; muscle tone ; mutation ; overeating ; pigmentation ; protein ; puberty ; rearrangement ; reproductive cells ; RNA ; short stature ; sign ; sperm ; stature ; symptom ; syndrome ; translocation ; uniparental disomy

You may find definitions for these and many other terms in the Genetics Home Reference Glossary.

See also Understanding Medical Terminology.

References (14 links)

출처: http://ghr.nlm.nih.gov/condition/prader-willi-syndrome

ㆍ부계염색체만 갖는 수정란은 염색체상 아무 이상이 없는 것처럼 보이지만 태아형성이 안되고, 태반이상이 초래됨(포상기태:hydatidiform)

포상기태 (Hydatidiform mole)

증상

비정상적 질출혈, 임신 오조증, 복부 통증, 구토, 거대자궁

진료과

산부인과

관련질환

비정상정 자궁, 질 출혈 , 유산

동의어

포도송이기태

0

0

정의

포상기태란 정자와 난자가 수정하여 태반을 형성하게 될 때 비정상적으로 융모가 과다 증식하면서 수포성 변성을 일으켜 작은 낭포를 형성하는 일종의 자궁 종양입니다. 포상기태의 태아는 수정란 발육 도중에 사망하여 소멸하는 경우가 대부분입니다.

원인

원인은 명확하게 밝혀지지 않았지만 태아의 염색체 이상 발생과 관계가 있는 것으로 알려지고 있습니다. 그리고 비타민 A의 섭취 부족이나 고령 임신, 단백질, 엽산 부족, 영양 부족 등이 위험 요인으로 지적되고 있습니다.

증상

가장 흔한 증상으로는 질출혈이 있으며 임신 중 과도한 입덧 증상을 나타낼 수도 있습니다. 골반통증이나 복강 내 출혈에 의한 심한 복통이 일어나기도 하고, 비정상적인 세포의 증식으로 자궁이 커지기 때문에 개월 수에 비해 배가 더 빠르게 나오는 것처럼 보입니다.

진단

포상기태는 임신호르몬 수치와 초음파로 진단할 수 있는데 혈중 융모성선자극호르몬의 증가가 정상 임신에 비해 과도히 증가되면 포상기태를 의심해 볼 수 있습니다. 절박 유산, 계류 유산, 자궁근종 등과 감별이 필요하며 확진은 소파 수술을 통하여 제거한 조직으로 조직검사를 시행합니다.

치료

치료로는 자궁 크기에 관계없이 흡입 소파술을 시행하게 됩니다. 간혹 수술 중 영양막 세포의 전이 예방 및 수술 후 악성화 빈도 감소 위해 포상기태 제거전이나 제거 중에 예방적 항암치료를 시행하기도 합니다. 포상기태의 치료 후 수개월에서 수 년(길게는 2년 이상)이 지나서 융모상피암이라는 악성 질환이 발생하는 수가 있기 때문에 수술 후 2년간은 정기적으로 산부인과 검진을 받는 것이 필요합니다.

출처; http://healthinfo.amc.seoul.kr/healthinfo/medical/diseaseView.do?kind=C000012&contentId=31935&diseaseId=H003160