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De novo truncating mutations in E6-AP ubiquitin-protein ligase gene (UBE3A) in Angelman syndrome

Nature Genetics volume 15, pages 7477 (1997) | Download Citation

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Abstract

Angelman syndrome (AS) is associated with maternal deletions of human chromosome 15q11–q13 and with paternal uniparental disomy for this region indicating that deficiency of an imprinted, maternally expressed gene within the critical interval is the likely cause of the syndrome. Although the gene for E6-AP ubiquitin-protein ligase (UBE3A) was mapped to the critical region for AS, evidence of expression from both parental alleles initially suggested that it was an unlikely candidate gene for this disorder. Because attempts to identify any novel maternally expressed transcripts were unsuccessful and because the UBE3A gene remained within a narrowed AS critical region, we searched for mutations in UBE3A in 11 AS patients without known molecular defects (large deletion, uniparental disomy, or imprinting mutation). This analysis tested the possibility that deficiency of an undefined, maternally expressed transcript or isoform of the UBE3A gene could cause AS. Four mutations were identified including a de novo frameshift mutation and a de novo nonsense mutation in exon 3 and two missense mutations of less certain significance. The de novo truncating mutations indicate that UBE3A is the AS gene and suggest the possibility of a maternally expressed gene product in addition to the biallelically expressed transcript. Intragenic mutation of UBE3A in AS is the first example of a genetic disorder of the ubiquitin-dependent proteolytic pathway in mammals. It may represent an example of a human genetic disorder associated with a locus producing functionally distinct imprinted and biallelically expressed gene products.

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Author information

Affiliations

  1. Departments of Molecular and Human Genetics, Howard Hughes Medical Institute, Baylor College of Medicine, One Baylor Plaza, Room T619, Houston, TX 77030, USA.

    • Toshinobu Matsuura
    • , James S. Sutcliffe
    • , Ping Fang
    • , Robert-Jan Galjaard
    • , Yong-hui Jiang
    •  & Arthur L. Beaudet
  2. Department of Pediatrics, Baylor College of Medicine & Houston, Texas 77030, USA.

    • Claudia S. Benton
  3. Howard Hughes Medical Institute, Houston, Texas 77030, USA.

    • Toshinobu Matsuura
    •  & Arthur L. Beaudet
  4. Department of Genetics, The Hospital for Sick Children and Department of Molecular and Medical Genetics, University of Toronto, Toronto Ontartio M5G1X8, Canada. T.M.,J.S.S., & P.P. contributed equally to this work.

    • Johanna M. Rommens

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Correspondence to Arthur L. Beaudet.

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DOI

https://doi.org/10.1038/ng0197-74

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