UBE3A E6-AP MUTATIONS CAUSE ANGELMAN SYNDROME

Angelman syndrome (AS), characterized by mental retardation, seizures, frequent smiling and laughter, and abnormal gait, is one of the best examples of human disease in which genetic imprinting plays a role(1). In about 70% of cases, AS is caused by de novo maternal deletions at 15q11-q13 (ref, 2), Approximately 2% of AS cases are caused by paterna l uniparental disomy (UPD) of chromosome 15 (ref, 3) and 2-3% are caus ed by imprinting mutations'(4). In the remaining 25% of AS cases, no d eletion, uniparental disomy (UPD), or methylation abnormality is detec table, and these cases, unlike deletions or UPD, can be familial(5-7). These cases are likely to result from mutations in a gene that is exp ressed either exclusively or preferentially from the maternal chromoso me 15. We have found that a 15q inversion inherited by an AS child fro m her normal mother disrupts the 5' end of the UBE3A (E6-AP) gene, the product of which functions in protein ubiquitination(15). We have loo ked for novel UBE2A mutations in nondeletion/non-UPD/non-imprinting mu tation (NDUI) AS patients and have found one patient who is heterozygo us for a 5-bp de novo tandem duplication, We have also found in two br others a heterozygous mutation, an A to G transition that creates a ne w 3' splice junction 7 bp upstream from the normal splice junction. Bo th mutations are predicted to cause a frameshift and premature termina tion of translation. Our results demonstrate that UBE3A mutations are one cause of AS and indicate a possible abnormality in ubiquitin-media ted protein degradation during brain development in this disease.