An individual with Prader-Willi syndrome caused by a deletion (15q11) produced a

Question

An individual with Prader-Willi syndrome caused by a deletion (15q11) produced an offspring with Angelman syndrome. Explain the underlying cause of each syndrome in these individuals. Give the sex of the parent with Prader-Willi syndrome syndrome and of the offspring with Angelman syndrome. Most cases of Prader-Willi syndrome (75%) are the result of a deletion, however in 25% of individuals with the syndrome there is no deletion present. Speculate as to the possible cause of Prader-Willi syndrome in the absence of a deletion.

Explanation / Answer

Chromosome 15q11-q13 region harbors several imprinted genes (genes are expressed preferentially from one parental allele). As a result, imprinted genes subject are functionally haploid. They have only one single functional copy. Angelman (AS) syndrome and Prader-Willi syndrome (PWS) occur due to deletions or duplications in this region.

PWS is caused by loss of paternally-inherited chromosome 15q11.2-q13 due to a large deletion in this region, or inheritance of both copies from mother (maternal uniparental disomy) or the paternal allele to behave as if it is inherited from the mother. Most PWS patients have loss of nearly 20 genes such as Necdin (NDN), Makorin ring 3 (MKRN3), Mage-like 2 (MAGEL2), PWRN2, PWRN1 etc.

Angelman syndrome (AS) is caused by lack of function of maternal UBE3A. This loss may be either due deletion of maternal 15q11.2-q13 or loss of function mutation of maternal UBE3A or paternal uniparental disomy or an imprinting defect. AS is a single gene disorder due to loss of UBE3A gene. UBE3A is a E3 ubiquitin ligase that adds lysine 48 (K48)-linked polyubiquitin chains to its substrates. Hence, the protein is targeted for protesomal degradation.

AS, and PWS, involve missing or silenced genes in this region, called the Prader-Willi critical region (PWCR: chromosome 15q11.2-q13). In a mother with PWS due to deletion in one of two copies of this chromosome, there is a 50% risk that her child will be born with AS. The reason is that one of the father's genes in this region of chr 15 is turned off or inactivated (imprinted). Hence, the child will have no active copies of this gene. This results in AS syndrome in child. However, if the normal copy of chr 15 is passed, the child will be normal. If the father has PWS due to deletion in chr15, the child has a 50% chance of developing PWS. This is because the mother’s genes in this region are inactivated or imprinted. Thus, this child will have PWS as it will have no functional copies of these genes.

Thus, the parent is the mother or the female. As AS is autosomal dominant modified by imprinting, it is not sex linked. Hence, it is equally common in both males and females. Hence, the child can be either a male or female.

When there is no deletion of the Chromosome 15q11.2-q13, the inheritance may be due to maternal uniparental disomy. In this, the individual receives two copies of the maternal chromosome instead of one copy from each parent. PWS can be rarely caused by a chromosomal translocation, or by mutations that inactivate the genes on the paternal chromosome 15.

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