Open Close
General Information
Name
Angelman syndrome
FlyBase ID
FBhh0000081
Disease Ontology Term
Parent Disease
Overview

This report describes Angelman syndrome; the human gene implicated in this disease is UBE3A, which encodes the ubiquitin protein ligase E3A. UBE3A acts in the ubiquitin proteasome pathway and as a transcriptional coactivator; the UBE3A gene is subject to genomic imprinting. There is a single orthologous gene in Drosophila, Dmel\Ube3a, for which classical amorphic alleles, RNAi targeting constructs, and alleles caused by insertional mutagenesis have been generated. The human UBE3A gene has also been identified as a susceptibility locus for autism spectrum disorder (FBhh0000515); loss or reduction of UBE3A function appears to result in Angelman syndrome, whereas increased activity due to extra copies or specific missense mutations are implicated in autism spectrum disorder.

Multiple UAS constructs of the human Hsap\UBE3A gene have been introduced into flies, representing different protein isoforms of the wild-type UBE3A gene. Heterologous rescue (functional complementation) of loss-of-function larval learning defects has been demonstrated.

Animals homozygous for amorphic mutations of Dmel\Ube3a are viable and fertile, however, they have neuroanatomy abnormalities and show defects in locomotive behavior, circadian rhythms, and long-term memory. Both up-regulation of and down-regulation of Ube3a are detrimental to learning in larvae and adults, and both deficiency and neural over-expression of Ube3a alters neurotransmission at the larval neuromuscular junction. RNAi-effected loss of function leads to reduced behavioral flexibility as shown by severe reversal-learning impairment. Genetic and physical interactions for Dmel\Ube3a have been described; see below and in the Ube3a gene report.

A number of human variants postulated to be associated with Angelman syndrome have been introduced as analogous mutations in the fly gene and characterized for neural and learning phenotypes. Variant(s) implicated in human disease tested (as analogous mutation in fly gene): C55Y in the fly Ube3a gene (corresponds to C44Y in the human UBE3A gene); C941A in the fly Ube3a gene (corresponds to C843A in the human UBE3A gene); T447P in the fly Ube3a gene (corresponds to S372P in the human UBE3A gene); I925K in the fly Ube3a gene (corresponds to I827K in the human UBE3A gene); R626C in the fly Ube3a gene (corresponds to R529C in the human UBE3A gene).

[updated Oct. 2019 by FlyBase; FBrf0222196]

Disease Summary Information
Disease Summary: Angelman syndrome
OMIM report

[ANGELMAN SYNDROME; AS](https://omim.org/entry/105830)

Human gene(s) implicated

[UBIQUITIN-PROTEIN LIGASE E3A; UBE3A](https://omim.org/entry/601623)

Symptoms and phenotype

Angelman syndrome is a neurodevelopmental disorder characterized by mental retardation, movement or balance disorder, typical abnormal behaviors, and severe limitations in speech and language. [From OMIM:105830, 2015.12.18]

Angelman syndrome (AS) is characterized by severe developmental delay or intellectual disability, severe speech impairment, gait ataxia and/or tremulousness of the limbs, and a unique behavior with an inappropriate happy demeanor that includes frequent laughing, smiling, and excitability. Microcephaly and seizures are also common. Developmental delays are first noted at around age six months; however, the unique clinical features of AS do not become manifest until after age one year, and it can take several years before the correct clinical diagnosis is obvious. [from GeneReviews, Angelman Syndrome, pubmed:20301323 2015.12.18]

Genetics

Four known genetic mechanisms can cause Angelman syndrome (AS). Approximately 70% of AS cases result from de novo maternal deletions involving chromosome 15q11.2-q13; approximately 2% result from paternal uniparental disomy of 15q11.2-q13; and 2 to 3% result from imprinting defects. A subset of the remaining 25% are caused by mutations in UBE3A, the gene encoding the ubiquitin-protein ligase E3A (Kishino et al., 1997, pubmed:8988171). [From OMIM:105830, 2015.12.18]

Cellular phenotype and pathology
Molecular information

UBE3A functions as both an E3 ligase in the ubiquitin proteasome pathway and as a transcriptional coactivator. The UBE3A gene is subject to genomic imprinting, with preferential maternal-specific expression in brain and, more specifically, in neurons but not in glia (Dindot et al., 2008, pubmed:17940072). UBE3A maps within the critical region for Angelman syndrome on chromosome 15q11-q13 (Matsuura et al., 1997, pubmed:8988172). [From OMIM:601623, 2015.12.18]

External links
Disease synonyms
Angelman syndrome; AS
AS
happy puppet syndrome
intellectual disability
marionette joyeuse
pantin hilare
Ortholog Information
Human gene(s) in FlyBase
Human gene (HGNC)
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)

One to one: 1 human to 1 Drosophila.

Other mammalian ortholog(s) used
    D. melanogaster Gene Information (1)
    Gene Snapshot
    Ubiquitin protein ligase E3A (Ube3a) encodes the founding member of the HECT-type ubiquitin E3 ligase family of enzymes. It is involved in the final step of conjugation of ubiquitin to its target substrates. It regulates protein degradation by targeting modified proteins to the proteasome or by regulating the proteasome activity through ubiquitination of its subunits, which in turn affects many aspects of neuronal function, such as synaptic plasticity, long-term memory or dendritic development. [Date last reviewed: 2019-02-28]
    Molecular function (GO)
    Cellular component (GO)
    Gene Groups / Pathways
    Comments on ortholog(s)

    Ortholog of human UBE3A (1 Drosophila to 1 human).

    Dmel\Ube3a shares 41% identity and 57% similarity with human UBE3A.

    Orthologs and Alignments from DRSC
    DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
    Other Genes Used: Viral, Bacterial, Synthetic (0)
      Summary of Physical Interactions (5 groups)
      protein-protein
      Interacting group
      Assay
      References
      enzymatic study, western blot
      anti tag coimmunoprecipitation, anti tag western blot
      anti tag coimmunoprecipitation, anti tag western blot
      enzymatic study, western blot, anti tag coimmunoprecipitation, anti tag western blot
      anti tag coimmunoprecipitation, anti tag western blot
      Alleles Reported to Model Human Disease (Disease Ontology) (14 alleles)
      Models Based on Experimental Evidence ( 12 )
      Modifiers Based on Experimental Evidence ( 2 )
      Allele
      Disease
      Interaction
      References
      is ameliorated by Mad12
      is ameliorated by tkv8
      is ameliorated by tkvk16713
      Models Based on Experimental Evidence ( 2 )
      Modifiers Based on Experimental Evidence ( 1 )
      Allele
      Disease
      Interaction
      References
      Alleles Representing Disease-Implicated Variants
      Genetic Tools, Stocks and Reagents
      Sources of Stocks
      Contact lab of origin for a reagent not available from a public stock center.
      Bloomington Stock Center Disease Page
      Selected mammalian transgenes
      Allele
      Transgene
      Publicly Available Stocks
      Selected Drosophila transgenes
      Allele
      Transgene
      Publicly Available Stocks
      RNAi constructs available
      Allele
      Transgene
      Publicly Available Stocks
      Selected Drosophila classical alleles
      Allele
      Allele class
      Mutagen
      Publicly Available Stocks
      amorphic allele - molecular evidence
      P-element activity
      amorphic allele - molecular evidence
      P-element activity
      amorphic allele - molecular evidence
      P-element activity
      amorphic allele - molecular evidence
      Delta2-3 transposase
      amorphic allele - molecular evidence
      P-element activity
      amorphic allele - molecular evidence
      ethyl methanesulfonate
      amorphic allele - molecular evidence
      ethyl methanesulfonate
      References (28)