UBE3A/E6-AP mutations cause Angelman syndrome

Nat Genet. 1997 Jan;15(1):70-3. doi: 10.1038/ng0197-70.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Angelman Syndrome / genetics*
  • Base Sequence
  • Brain / embryology
  • Brain / enzymology
  • Chromosome Mapping
  • Chromosomes, Human, Pair 15
  • DNA, Complementary
  • Female
  • Frameshift Mutation
  • Genomic Imprinting
  • Humans
  • Ligases / genetics*
  • Male
  • Molecular Sequence Data
  • Mutation*
  • Pedigree
  • Polymorphism, Single-Stranded Conformational
  • Ubiquitin-Protein Ligases
  • Ubiquitins / metabolism


  • DNA, Complementary
  • Ubiquitins
  • UBE3A protein, human
  • Ubiquitin-Protein Ligases
  • Ligases

Associated data

  • GENBANK/U84404