Identification and characterisation of genes from the Angelman and Prader-Willi syndrome region of chromosome 15q11-13

Angelman syndrome (AS) and Prader-Willi syndrome (PWS) are clinically distinct neurobehavioural disorders which map to 15ql 1.2-12. AS is characterised by mental retardation, seizures, ataxia, absent speech, excessive laughter, and distinctive EEG. PWS involves poor suck reflex and hypotonia in infancy, short stature, microgenitalia, and hyperphagia leading to obesity. Chromosome 15ql 1.2-12 is subject to genomic imprinting whereby certain genes are functionally active or silent depending on their parental origin of inheritance. AS and PWS are caused by various mechanisms including cytogenetic deletion, uniparental disomy and altered epigenetic modification, with the common factor being lack of a maternal contribution to 15ql 1.2-12 in AS, and loss of expression of genes on the paternally derived allele in PWS. Approximately 25% of AS patients, including familial cases, are due to mutations of an imprinted gene within 15ql 1.2-12, which is expressed from the maternal allele. The UBE3A gene has been implicated in AS. The lack of a similar category of patients in PWS suggests that this is a contiguous gene disorder. In order to identify genes which may be involved in the pathogenesis of either AS or PWS, positional cloning studies were performed in the AS and distal portion of the PWS candidate regions. UBE3A was located to the AS region, and a novel expressed sequence identified through direct cDNA selection was shown to represent an extended 3' untranslated region of UBE3A. No additional genes were identified in the AS region. USES A was screened for mutations in cases of familial and sporadic AS in which the genetic aetiology of the disease remained unidentified. Pathogenic mutations were identified in 3/5 familial and 4/21 sporadic cases, indicating that UBE3A mutations cause AS in a proportion of patients. Two novel transcripts, '395-H22' and '123-E19', were identified from the PWS region. 395- H22 was found to be expressed solely from the paternal allele in an in vitro imprinting assay system, indicating that it may represent an additional gene involved in the PWS phenotype.