THE E6-AP UBIQUITIN-PROTEIN LIGASE (UBE3A) GENE IS LOCALIZED WITHIN ANARROWED ANGELMAN SYNDROME CRITICAL REGION

Angelman syndrome (AS) and Prader-Willi syndrome (PWS) are distinct cl inical phenotypes resulting from maternal and paternal deficiencies, r espectively, in human chromosome 15q11-q13. Although several imprinted , paternally expressed transcripts have been identified within the PWS candidate region, no maternally expressed gene has yet been identifie d within the AS candidate region. We have developed an integrated phys ical map spanning the PWS and AS candidate regions and localized two b reakpoints, including a cryptic t(14;15) translocation associated with AS and a non-AS 15q deletion, which substantially narrow the AS candi date region to similar to 250 kb. Mapping data indicate that the entir e transcriptional unit of the E6-AP ubiquitin-protein ligase (UBE3A) g ene lies within the AS region. The UBE3A locus expresses a transcript of similar to 5 kb at low to moderate levels in all tissues tested. Th e mouse homolog of UBE3A was cloned and sequenced revealing a high deg ree of conservation at nucleotide and protein levels. Northern and RT- PCR analysis of Ube3a expression in mouse tissues from animals with se gmental, paternal uniparental disomy failed to detect substantially re duced or absent expression compared to control animals, failing to pro vide any evidence for maternal-specific expression from this locus. Re cent identification of de novo truncating mutations in UBE3A taken wit h these observations indicates that mutations in UBE3A can lead to AS and suggests that this locus may encode both imprinted and biallelical ly expressed products.