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Biochemistry

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Purines, Pyrimidines and Nucleic Acid Metabolism

Question
28 out of 59
 

Maternal disomy is found in? (AIIMS Nov 2010)



A Prader Willi syndrome

B Angelman syndrome

C Fragile X syndrome

D Hydatiform mole

Ans. A Prader Willi syndrome

a. Maternal uniparental disomy for chromosome 15 [upd(15)mat] is the second most common finding in patients with Prader–Willi syndrome (PWS).

b. PWS is characterized by neonatal hypotonia, hypogonadism, hyperphagia leading to obesity, short stature, small hands and feet, behavioral problems and mental retardation.

c. Patients with upd (15)mat have two copies of all genes on chromosome 15, but they lack the activity of imprinted genes expressed from the paternal chromosome only (MKRN3, AGEL2, NDN, SNURF-SNRPN and several snoRNA genes) and have a double dose of imprinted genes expressed from the maternal copy only (UBE3A and ATP10C), although the expression levels of the latter two genes has not been determined in these patients.

d. The imprinted gene cluster within 15q11–q13 is under the coordinated control of an imprinting center.

e. Apart from sychosis , there is no significant clinical difference between patients with upd(15)mat and patients with a paternal deletion of 15q11–q13 .

f. Therefore it is generally assumed that it is the loss of function of one or more paternally expressed genes rather than increased expression of a maternally expressed gene that is responsible for the major clinical findings. It is unclear, however, which of the paternally expressed genes are relevant for PWS and which pathways are affected.

g. A good candidate for the ‘PWS gene(s)’ are the HBII-85 snoRNA genes, which are located within the SNURFSNRPN transcription unit .

h. These genes are expressed predominantly in brain, but in other tissues as well. It has been suggested that the HBII-85 snoRNAs are involved in alternative splicing or mRNA editing , but the target RNAs have remained elusive.

i. Maternal uniparental disomy most often results from a combination of meiotic and mitotic errors .

j. Non-disjunction of the homologous chromosomes 15 during female meiosis I or non-disjunction of the two sister chromatids during female meiosis II results in an oocyte with two chromosomes 15.

k. Fertilization of such an oocyte by a sperm with one chromosome 15 will result in a zygote which is trisomic for chromosome 15.

l. This condition is not compatible with normal development, but can be rescued by loss of one chromosome 15 (trisomy rescue).

m. In two-thirds of cases, one of the two maternal chromosomes will be lost from the trisomic cell.

n. This will result in a normal set of chromosomes. If , however, the paternal chromosome is lost, the cell is left with two maternal chromosomes 15.

o. The trisomic cell line is often found to be confined to the placenta, but has occasionally been observed in the fetus also .

p. In women with upd, X inactivation is often skewed, indicating that trisomy rescue occurred after X inactivation.

q. Most cases of Prader-Willi syndrome (about 70 percent) occur when a segment of the paternal chromosome 15 is deleted in each cell. 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.

r. 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.

s. Each of these genetic changes results in a loss of gene function in a critical region of chromosome 15.

(ANGEL MAM SYNDROME)

Paternal uniparental disomy [upd(15)pat] results from the fertilization of an oocyte that is nullisomic for chromosome 15 and the postzygotic duplication of the paternal chromosome. Upd(15)pat is associated with the loss of function of the maternally expressed UBE3A gene, which leads to Angelman syndrome (AS).

a. Angelman syndrome (AS) is a neurological disorder first described in 1965 by an English physician named Dr. Harry Angelman.

b. Symptoms are usually evident after the age of three, and are characterized by severe congenital mental retardation, unusual facial appearance, and muscular abnormalities.

c. A very small area in ch 15 is deleted in patients with Angelman Syndrome.

d. This deleted area contains genes that are activated or inactivated (turned on or off) depending upon which parent the chromosome was inherited from.

e. The Angelman Syndrome gene is called UBE3A. When this gene is turned on, Angelman Syndrome does not occur.

f. However, when it is turned off or missing, Angelman Syndrome occurs.

g. In patients with Angelman Syndrome, a missing UBE3A gene only occurs in the chromosome given by the mother.

h. For this reason, it seems that the UBE3A gene is turned on only on the chromosome inherited from mother.

i. Researchers have also found that Angelman Syndrome is caused when a child inherits both chromosomes 15 from the father.

j. This condition is called paternal uniparental disomy (UPD). In this case, both chromosomes have turned off UBE3A genes on them.

k. There is a control region, called the Imprinting Center (IC), that can control or turn on or off the action of the UBE3A gene.

l. Mutations in the area of the Imprinting Center can also cause Angelman Syndrome.

Purines, Pyrimidines and Nucleic Acid Metabolism Flashcard List

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