title: Mutation of HERC2 causes developmental delay with Angelman-like features.
abstract: 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.
  
  
  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.
authors.affiliation: Centre for Human Genetics, St George's University of London, London, UK.
authors.forename: Gaurav V
authors.initials: GV
authors.lastname: Harlalka
authors.forename: Emma L
authors.initials: EL
authors.lastname: Baple
authors.forename: Harold
authors.initials: H
authors.lastname: Cross
authors.forename: Simone
authors.initials: S
authors.lastname: Kühnle
authors.forename: Monica
authors.initials: M
authors.lastname: Cubillos-Rojas
authors.forename: Konstantin
authors.initials: K
authors.lastname: Matentzoglu
authors.forename: Michael A
authors.initials: MA
authors.lastname: Patton
authors.forename: Karin
authors.initials: K
authors.lastname: Wagner
authors.forename: Roselyn
authors.initials: R
authors.lastname: Coblentz
authors.forename: Debra L
authors.initials: DL
authors.lastname: Ford
authors.forename: Deborah J G
authors.initials: DJ
authors.lastname: Mackay
authors.forename: Barry A
authors.initials: BA
authors.lastname: Chioza
authors.forename: Martin
authors.initials: M
authors.lastname: Scheffner
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Rosa
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Crosby
mesh_terms: D000293:Adolescent; D000328:Adult; D061365:Amish / Q000235:genetics*; D017204:Angelman Syndrome / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000737:chemistry; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000032:analysis / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D005347:Fibroblasts / Q000737:chemistry / Q000378:metabolism; D055106:Genome-Wide Association Study; D020662:Guanine Nucleotide Exchange Factors / Q000097:blood / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007223:Infant; D008297:Male; D008958:Models, Molecular; D009154:Mutation; D009687:Nuclear Proteins / Q000737:chemistry; D010375:Pedigree; D044767:Ubiquitin-Protein Ligases
chemical_list: D018797:Cell Cycle Proteins; D020662:Guanine Nucleotide Exchange Factors; D009687:Nuclear Proteins; C062521:RCC1 protein, human; D004247:DNA; C118566:HERC2 protein, human; D044767:Ubiquitin-Protein Ligases