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UBE3A/E6-AP mutations cause Angelman syndrome

Nature Geneticsvolume 15pages7073 (1997) | Download Citation


  • An Erratum to this article was published on 01 April 1997


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 role1. 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’ 4. 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 familial5–7. 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 ubiquitination16. 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.

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  1. Genetics Division, Children's Hospital and Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts, 02115, USA

    • Tatsuya Kishino
    • , Marc Lalande
    •  & Joseph Wagstaff
  2. Howard Hughes Medical Institute, Boston, Massachusetts, USA

    • Marc Lalande


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