title: UBE3A/E6-AP mutations cause Angelman syndrome.
abstract: 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. 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 paternal uniparental disomy (UPD) of chromosome 15 (ref. 3) and 2-3% are caused by "imprinting mutations'. In the remaining 25% of AS cases, no deletion, uniparental disomy (UPD), or methylation abnormality is detectable, and these cases, unlike deletions or UPD, can be familial. These cases are likely to result from mutations in a gene that is expressed either exclusively or preferentially from the maternal chromosome 15. We have found that a 15q inversion inherited by an AS child from her normal mother disrupts the 5' end of the UBE3A (E6-AP) gene, the product of which functions in protein ubiquitination. We have looked for novel UBE3A mutations in nondeletion/non-UPD/non-imprinting mutation (NDUI) AS patients and have found one patient who is heterozygous for a 5-bp de novo tandem duplication. We have also found in two brothers a heterozygous mutation, an A to G transition that creates a new 3' splice junction 7 bp upstream from the normal splice junction. Both mutations are predicted to cause a frameshift and premature termination of translation. Our results demonstrate that UBE3A mutations are one cause of AS and indicate a possible abnormality in ubiquitin-mediated protein degradation during brain development in this disease.
authors.affiliation: Genetics Division, Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: T
authors.initials: T
authors.lastname: Kishino
authors.forename: M
authors.initials: M
authors.lastname: Lalande
authors.forename: J
authors.initials: J
authors.lastname: Wagstaff
mesh_terms: D000595:Amino Acid Sequence; D017204:Angelman Syndrome / Q000235:genetics*; D001483:Base Sequence; D001921:Brain / Q000196:embryology / Q000201:enzymology; D002874:Chromosome Mapping; D002884:Chromosomes, Human, Pair 15; D018076:DNA, Complementary; D005260:Female; D016368:Frameshift Mutation; D018392:Genomic Imprinting; D006801:Humans; D008025:Ligases / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D018807:Polymorphism, Single-Stranded Conformational; D044767:Ubiquitin-Protein Ligases; D014452:Ubiquitins / Q000378:metabolism
chemical_list: D018076:DNA, Complementary; D014452:Ubiquitins; C471639:UBE3A protein, human; D044767:Ubiquitin-Protein Ligases; D008025:Ligases