Exclusion of SNRPN as a major determinant of Prader-Willi syndrome by a translocation breakpoint

The predominant genetic defects in Prader-Willi syndrome (PWS) are 15q11-q13 deletions of paternal origin and maternal chromosome 15 uniparental disomy (UPD). In contrast, maternal deletions and paternal chromosome 15 UPD are associated with a different neurogenetic disorder, Angelman syndrome (AS). In both disorders, these mutations are associated with parent-of-origin specific methylation at several 15q11-q13 loci. The critical PWS region has been narrowed to a approximately 320-kb region between D15S63 and D15S174, encoding several imprinted transcripts, including PAR5, IPW, PAR1 (refs 7,8) and SNRPN, which has so far been considered a strong candidate for the PWS gene. A few PWS-associated microdeletions involving a putative imprinting centre (IC) proximal to SNRPN have also been observed. We have mapped the breakpoint of a balanced translocation (9;15)pat associated with most of the PWS features between SNRPN and IPWIPAR1. Methylation and expression studies indicate that the paternal SNRPN allele is unaffected by the translocation, while IPW and PAR1 are unexpressed. This focuses the attention on genes distal to the breakpoint as the main candidate for PWS genes, and is consistent with a cis action of the putative IC, and suggests that further studies of translocational disruption of the imprinted region may establish genotype-phenotype relationships in this presumptive contiguous gene syndrome.