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Mutation of HERC2 causes developmental delay with Angelman-like features
  1. Gaurav V Harlalka1,
  2. Emma L Baple1,
  3. Harold Cross2,
  4. Simone Kühnle3,
  5. Monica Cubillos-Rojas4,
  6. Konstantin Matentzoglu3,
  7. Michael A Patton1,
  8. Karin Wagner5,
  9. Roselyn Coblentz5,
  10. Debra L Ford6,
  11. Deborah J G Mackay7,
  12. Barry A Chioza1,
  13. Martin Scheffner3,
  14. Jose Luis Rosa4,
  15. Andrew H Crosby1
  1. 1Centre for Human Genetics, St. George's, University of London, London, UK
  2. 2Department of Ophthalmology and Vision Science, College of Medicine, University of Arizona, Tucson, Arizona, USA
  3. 3Department of Biology and Konstanz Research School Chemical Biology, University of Konstanz, Konstanz, Germany
  4. 4Departament de Ciències Fisiològiques II, IDIBELL, Campus de Bellvitge, Universitat de Barcelona, L'Hospitalet del Llobregat, Barcelona, Spain
  5. 5Windows of Hope Genetic Study, Holmes County, Ohio, USA
  6. 6Verde Valley Guidance Clinic, Cottonwood, Arizona, USA
  7. 7Division of Human Genetics, University of Southampton, Southampton, UK
  1. Correspondence to Dr Andrew H Crosby, Centre for Human Genetics, St George's University of London, Cranmer Terrace, SW17 0RE London, UK; acrosby{at}


Background Deregulation of the activity of the ubiquitin ligase E6AP (UBE3A) is well recognised to contribute to the development of Angelman syndrome (AS). The ubiquitin ligase HERC2, encoded by the HERC2 gene is thought to be a key regulator of E6AP.

Methods and results Using a combination of autozygosity mapping and linkage analysis, we studied an autosomal-recessive neurodevelopmental disorder with some phenotypic similarities to AS, found among the Old Order Amish. Our molecular investigation identified a mutation in HERC2 associated with the disease phenotype. We establish that the encoded mutant HERC2 protein has a reduced half-life compared with its wild-type counterpart, which is associated with a significant reduction in HERC2 levels in affected individuals.

Conclusions Our data implicate a model in which disruption of HERC2 function relates to a reduction in E6AP activity resulting in neurodevelopmental delay, suggesting a previously unrecognised role of HERC2 in the pathogenesis of AS.

  • Developmental
  • Clinical genetics
  • Neurosciences

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