A novel missense mutation of the ubiquitin protein ligase E3A gene in a patient with Angelman syndrome.

Background: Angelman syndrome (AS) is a neurogenetic disorder caused by an expression defect of the maternally inherited copy of ubiquitin protein ligase E3A (UBE3A) gene from chromosome 15. Although the most common genetic defects include maternal deletions of chromosome 15q11-13, paternal uniparental disomy and imprinting defect, mutations in the UBE3A gene have been identified in approximately 10% of AS patients.

Methods: A Chinese girl of 28 months presented clinical manifestation of AS. Genetic diagnosis and molecular genetic defects were studied by methylation-specific PCR (MS-PCR) and linkage analysis by short tandem repeat (STR). We further performed sequence analysis of all the coding exons and flanking sequences of the UBE3A gene. The novel mutation screening was also performed in 100 unrelated healthy individuals to exclude the possibility of identifying a polymorphism variation.

Results: The MS-PCR analysis of the patient showed biparental inheritance of chromosome 15 with a normal methylation pattern in the 15q11-q13 region. And STR analysis revealed that the patient also inherited biparental alleles for six microsatellites. A novel mutation, cDNA1199 C> A (p.P400H), in exon 9 of the maternal UBE3A gene, was identified in the patient. Meanwhile, the mutation was observed in the patient's mother who had a normal phenotype.

Conclusions: It is necessary to perform the UBE3A gene mutation analysis in non-deletion/non-UPD/non-ID patients with AS. The clinical picture of the patient is concordant with that observed in previously reported AS patients with UBE3A mutation.