Prader-Willi Syndrome and Angelman Syndrome?

Question

On the website http://www.whatisepigenetics.com/fundamentals/2/ it states that

the imprint disorders Prader-Willi syndrome and Angelman syndrome, display an abnormal phenotype as a result of the absence of the paternal or maternal copy of a gene, respectively. In these imprint disorders, there is a genetic deletion in chromosome 15 in a majority of patients. The same gene on the corresponding chromosome cannot compensate for the deletion because it has been turned off by methylation, an epigenetic modification. Genetic deletions inherited from the father result in Prader-Willi syndrome, and those inherited from the mother, Angelman syndrome.

To me it seems like this is suggesting the same problem in both Prader-Willi and Angelman sydrome- lack of expression of a particular gene. However in Prader-Willi syndrome it is the paternal chromosome that is missing and the maternal copy of this gene is silenced by methylation and the reverse applies for Angelman syndrome. Therefore it seems that in boh cases the problem is the lack of expression of this gene. Why, then, if both are caused by lack of expression of this gene, do these two illnesses have such different symptoms (constant hunger in Prader-Willi syndrome and mental disability and jerky movements in Angelman syndrome)?

Answer 1

Within that region, there are multiple genes.

Although the same gene may control imprinting for both disorders, the gene(s) causing their phenotypes differ. AS results from underexpression of a single gene, UBE3A, which codes for E6-AP, a protein that functions to transfer small ubiquitin molecules to certain target proteins, to enable their degradation. The genes responsible for PWS are not determined, although several maternally imprinted genes in 15q11-q13 are known. The most likely candidate is SNRPN

From this paper: http://www.ncbi.nlm.nih.gov/pubmed/11180221

Answer 2

In a wild-type human, you will inherit one paternal chromosome and one maternal chromosome, in this case, chromosome 15.

The paternal chromosome which is packaged into the sperm will be methylated in such a way that the Ubiqitin-Protein Ligase E3A (UBE3A) gene is silenced.

The maternal chromosome which is packaged into the oocyte will be methylated in such a way that the Small Nuclear Ribonucleoprotein Polypeptide N (SNRPN) and NECDIN (NDN) genes are silenced.

When the egg is fertilized, it has the paternal chromosome and the maternal chromosome, which complement each other (The same as a genetic complementation test would).

In a wild-time embryo, UBE3A is expressed off of the maternal chromosome, and SNRPN and NDN will be expressed from the paternal chromosome, and the wild-type phenotype will be rescued.

So in Prader-Willi Syndrome, at some point in time, the DNA that went into the male gamete sustained a deletion at 15q11, so the entire locus, with those three genes was lost. If that sperm then fertilizes an egg, the paternal chromosome no longer has SNRPN and NDN to rescue the wild-type phenotype. Because those genes are silenced on the maternal chromosome and deleted on the paternal chromosome, there is no allele available to express the relevant gene product. In effect, this embryo will be the equivalent of null/null for SNRPN and NDN.

Then in Angelman Syndrome, the opposite situation is in effect. The DNA that went into the female gamete sustained a deletion at 15q11, so the entire locus, with those three genes was lost. If that egg is fertilized, then the maternal chromosome will not be available to rescue the wild-type phenotype because the UBE3A is silenced on the paternal chromosome. In effect, this embryo will be the equivalent of null/null for UBE3A

So in effect Prader-Willi Syndrome is the phenotype for the SNRPN and NDN null/null mutant and Angelman Syndrome is the phenotype for the UBE3A null/null mutant.

Even though the genes are present on one of the alleles, the sex determined imprinting causes different genes to be silence, so that is why the same deletion is able to produce two different phenotypes, depending on which gamete that forms the embryo sustains the deletion.

Answer 3

Both Prader-Willi and Angelman syndrome can also occur as a result of having both members of the chromosome 15 pair derived from 1 parent, a condition known as uniparental disomy. Both can also result from a structural abnormality of the imprinting center, known as an imprinting mutation. In addition, Angelman syndrome can be caused by a mutation in the gene that causes it; a comparable cause is not present in Prader-Willi syndrome since it results from abnormality in more than 1 gene.

See details: https://thehealthbd.com/prader-willi-syndrome/