by Alice Ren
Prader-Willi syndrome and Angelman syndrome (PWS and AS respectively) are two clinically distinct conditions, often discussed together due to both diseases involving uniparental disomy and genomic imprinting on the same chromosome, #15. Both PWS and AS involve abnormality in the section 15q11-q13 of this chromosome. Why is this so significant, you may wonder? Due to the abnormal genetic basis of these conditions and being among the first incidences in which two completely distinct syndromes have such similar, almost parallel causes, PWS and AS played a huge role in the research of genetic disorders and genomic imprinting. Let’s take a deeper look into how this happened.
PWS is a genetic disorder that causes a variety of physical problems, behavioural issues and learning difficulties, and is often discovered in newborn babies. Its symptoms include excessive appetite / overeating, restricted growth, hypotonia in muscles (muscle tone is diminished and becomes “floppy”) and lack of sexual development. PWS is caused by the deletion of the previously mentioned genetic material, 15q11-q13, on the paternally inherited copy of chromosome #15.
AS is also a genetic disorder, affecting mainly the nervous system. It causes physical and learning disabilities. Symptoms include hyperactivity, frequent laughter with no stimulus and frequent seizures / fits. We can see that the symptoms of AS are completely different to that of PWS, but its cause is strikingly similar: AS is also caused by the deletion of 15q11-q13 on chromosome #15, but this time it is deleted on the maternally inherited copy, unlike PWS.
So why does the parent of origin of the chromosome determine what disorder the deletion causes? The answer would be genomic imprinting. This is the process by which genes are expressed differently depending on which parent they came from. For the genes relevant to PWS, under normal circumstances (that is, when the disorder is not present), the maternally derived copies of these genes in 15q11-q13 are silenced, and the paternally derived copies are active, whereas for AS the paternally derived copies of these genes in 15q11-q13 are silenced and the paternally derived copies are active, whereas for AS, the paternally derived copies of the relevant genes in 15q11-q13 are normally silenced while the maternally derived copies are active. For both conditions, abnormality occurs when the copy of the gene in 15q11-q13 that is usually active, i.e. for PWS this would be the paternal copy and for AS it would be the maternal copy, is turned off by genomic imprinting (the specific mechanism of the imprinting is DNA methylation) or deleted. The loss of the active genes results in the manifestation of the relevant syndrome.
In AS, the deletion involves a gene involved in the ubiquitin pathway, called UBE3A. This gene codes for an enzyme of the same name (UBE3A) - the loss of this enzyme can cause the characteristic features of AS. As mentioned previously, normally the maternal gene is expressed while the paternal gene is silent. Because the maternal gene is now missing via either deletion (which accounts for 70% of AS patients) or other genetic abnormalities (30% of patients), the phenotypic symptoms of AS are expressed. The paternal gene is also unable to fill the blank caused by the loss of the maternal genes, because it has been silenced by genomic imprinting. This loss of the maternal contribution is what causes AS. However, it can also be caused by uniparental disomy. There have been rare cases in which the normally active maternal gene has been lost completely; thus both copies of the gene come from the father and none from the mother. Although both paternal copies are genetically normal, the genes relevant to AS are silent on both chromosomes, causing AS to occur.
In PWS, the deletion involves both UBE3A and other genes in the same region, including SNRPN. Contrary to AS, normally, the paternal gene is expressed while the maternal gene is silenced by genomic imprinting. The loss of the paternal gene causes PWS to occur, as the maternal gene cannot take its place. Again, PWS can also be caused by uniparental disomy, where two copies of the silent maternal chromosome are present, and none from the father. The silence in the genes relevant to PWS is what causes PWS.
Exploring PWS and AS has provided a great deal of information to researchers regarding the significance of genomic imprinting. It is fascinating to see that the parent of origin is so pivotal in the determination of which disorder develops. The diagram above illustrates clearly the abnormal genetic conditions involved in both PWS and AS.
Sources:
https://pubmed.ncbi.nlm.nih.gov/9556704/
https://www.urmc.rochester.edu/encyclopedia/content.aspx?ContentTypeID=90&ContentID=P02159
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