The genetic basis for Prader-Willi syndrome: the importance of imprinted genes

The genetic basis of Prader-Willi syndrome involves imprinted genes on the proximal long arm of chromosome 15. The basic defect appears to be the absence of function of genes that are normally expressed in a monoallelic fashion only from the paternal chromosome. In 60-70% of patients with Prader-Willi syndrome, the genetic defect is a deletion in the area of 15q11-13 on the paternal chromosome. A further 25-30% of patients with Prader-Willi syndrome do not have paternal deletions, the defect being due to uniparental disomy (UPD) for maternal chromosome 15. Paternal deletions and maternal UPD are functionally equivalent, as they both result in the absence of a paternal contribution to the genome in the 15q11-13 region. The SNRPN (small nuclear ribonucleoprotein-associated polypeptide N) gene has a critical role in the 15q11-13 region, as it is probably part of the putative imprinting centre that regulates the expression of several genes in the Prader-Willi syndrome transcriptional domain. Two further rare causes of Prader-Willi syndrome are imprinting mutations, which are microdeletions or point mutations in the putative imprinting control region, and translocations with their breakpoints in the Prader-Willi syndrome region.