Imprinted genes in the Prader-Willi deletion

Abstract

Parent-of-origin-specific deletions of proximal chromosome 15q cause either the Prader-Willi syndrome (paternal deletion) or the Angelman syndrome (maternal deletion), two distinct neurodevelopmental disorders. In contrast to the Angelman syndrome, which can also be caused by mutations in a single gene (UBE3A, encoding a ubiquitin ligase), the Prader-Willi syndrome is caused by deletions in about two-thirds of cases and by maternal uniparental disomy in the remaining third. The consequence of both mechanisms, in addition to rare microdeletions or so-called 'imprinting mutations', is lack of the products of multiple genes in the region that are normally expressed only from the paternal chromosome. One gene that is consistently silent in the Prader-Willi syndrome is SNRPN, which encodes the small nuclear ribonucleoprotein particle-associated polypeptide N that forms part of the spliceosomes in the brain. A systematic search for other imprinted genes in the Prader-Willi syndrome region revealed a paternally expressed transcript (IPW, for imprinted in the Prader-Willi region) and a similarly imprinted mouse homologue (Ipw) in the conserved syntenic region on mouse chromosome 7. Ipw is highly expressed in the brain and alternatively spliced to generate different transcripts. Since there is no open reading frame that is conserved in the human and mouse IPW genes, they are postulated to function as untranslated RNAs, possibly regulating transcription in cis in the region.