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GENATLAS PHENOTYPE
last update : 19-04-2011
Symbol AS
Location 15q11.2-q12
Name Angelman syndrome
Corresponding gene UBE3A , ATP10A , OCA2 , GABRB3
Other symbol(s) DEL15Q12, ANCR, UPD15P
Main clinical features
  • severe developmental delay/mental retardation, profound speech impairment, gait ataxia and/or movement disorder, characteristic behavioural profile including unprovoked prolonged paroxysms of laughther and excitability
  • other common features include seizures, abnormal EEG patterns, microcephaly, evocative facial features and hypopigmentation
  • distinct phenotypes distinguish the molecular classes of AS
    • Genetic determination chromosomal
    epigenetic
    genomic disorder
    Prevalence ~1/15000
    Function/system disorder multisystem/generalized
    mental retardation
    Type MCA/MR
    Gene product
    Name E6-AP ubiquitin protein ligase (UBE3A), expressed exclusively from the maternal allele in brain, defective expression in the ubiquitin-proteasome protein degradation pathway. Other genes expressed from the maternal chromosome include ATP10A, IC15, HERC2, SPG6, NIPA2, TUBGCP5.
    Mechanism(s)
    Gene mutationChromosome rearrangementEffectComments
      deletion absent protein typically deleted region ~4.8MB and ~5.7Mb in size on the maternal chromosome, type I between BP1-BP3, type II between BP2-BP3
      uniparental disomy absent protein paternal UPD15
    imprinting defect   absent protein microdeletions or LOI at the 5'end of the ICR
    various types   absent protein maternal UBE3A mutations
    unknown     unknown mechanism
      deletion   some unusually large deletions, the largest <10.6 Mb, including the APBA2, TJP1, TRPM1 and CHRNA7 genes, with a more severe phenotype
    Remark(s) - maternally-derived deletion in ~65-70 percent of cases, paternal UPD in ~5 percent, maternal UBE3A mutations in~10 percent, unknown defect in 10 percent
  • four known genes (NIPA1, NIPA2, CYFIP1 and GCP5) are affected by class I but not class II deletions
  • deficits observed in AS patients may result from specific abnormalities in synaptic development and/or plasticity
  • dendritic pathology may contribute to neurological deficits in patients with Angelman syndrome (PMID: 18996915))
  • UBE3A regulates excitatory synapse development by controlling the degradation of Arc, a synaptic protein that promotes the internalization of the AMPA subtype of glutamate receptors
  • results from loss of function of the ubiquitin protein ligase E3A (UBE3A) (PMID: 20876107))
    • Genotype/Phenotype correlations
  • deletion patients are the most severely affected with highest incidence of severe seizures and hypopigmentation, complete absence of speech, severe microcephaly and normal body mass index
  • UPD and ID patients are much less severely affected with a lower incidence of hypopigmentation, microcephaly and severe seizures, more than three words in their vocabulary, elevated body mass index
  • UBE3A mutation patients are similar to deletion patients with respect to seizures, absence of speech and microcephaly, and to UPD and ID patients in developmental milestones and high incidence of early onset obesity