The human gene UBE3A has been identified as a susceptibility locus for autism spectrum disorder (FBhh0000514) in a number of studies. Ube3a encodes the ubiquitin protein ligase E3A, which 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 is also implicated in Angelman syndrome (FBhh0000081); 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.
The human UBE3A gene is within a chromosomal region susceptible to duplication, the 15q11-q13 region (see MIM:608636). These duplications result in a spectrum of variable phenotypes described as chromosome 15q11-q13 region duplication syndrome; phenotypes include autism, mental retardation, ataxia, seizures, developmental delays, and behavioral problems. Little is known about how much UBE3A, as opposed to other genes within the duplicated region, contributes to the various phenotypes. The UBE3A gene has been shown to be subject to genomic imprinting.
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.
[updated Jan. 2021 by FlyBase; FBrf0222196]
Autism, the prototypic pervasive developmental disorder (PDD), is usually apparent by 3 years of age. It is characterized by a triad of limited or absent verbal communication, a lack of reciprocal social interaction or responsiveness, and restricted, stereotypic, and ritualized patterns of interests and behavior (Bailey et al., 1996, pubmed:8655659; Risch et al., 1999, pubmed:10417292). 'Autism spectrum disorder,' sometimes referred to as ASD, is a broader phenotype encompassing the less severe disorders Asperger syndrome (MIM:608638) and pervasive developmental disorder, not otherwise specified (PDD-NOS). 'Broad autism phenotype' includes individuals with some symptoms of autism, but who do not meet the full criteria for autism or other disorders. Mental retardation coexists in approximately two-thirds of individuals with ASD, except for Asperger syndrome, in which mental retardation is conspicuously absent (Jones et al., 2008; pubmed:18698615). [from MIM:209850; 2017.03.18]
Dup15q is characterized by hypotonia and motor delays, intellectual disability, autism spectrum disorder (ASD), and epilepsy including infantile spasms. [Gene Reviews, 15q Duplication Syndrome and Related Disorders; 2020.08.29]
Deletion of UBE3A causes the neurodevelopmental disorder Angelman syndrome (AS); maternally-derived duplication or triplication of UBE3A is linked to autism; some missense mutations have been characterized (Yi et al., 2015; pubmed:26255772 and references cited therein).
UBE3A is imprinted with maternal-specific expression in postnatal neurons, and thus expressed at a higher dosage in brain from individuals with a maternally derived duplication. [Gene Reviews, 15q Duplication Syndrome and Related Disorders; 2021.01.10]
The SFARI Gene autism database ( https:gene.sfari.org ) rates the gene-autism association for UBE3A as high confidence (score 1). [2020.11.05]
The proximal 15q region includes five regions of segmental duplications or low copy repeats (designated by breakpoints [BPs]), which result in increased susceptibility to genomic rearrangements. These five regions are termed BP1 through BP5. The Prader-Willi/Angelman critical region (PWACR) lies between BP2 and BP3; UBE3A lies within the PWACR. [Gene Reviews, 15q Duplication Syndrome and Related Disorders; 2021.01.10]
The human UBE3A gene is within a chromosomal region susceptible to duplication, the 15q11-q13 region. These duplications result in a spectrum of variable phenotypes described as chromosome 15q11-q13 region duplication syndrome; phenotypes include autism, mental retardation, ataxia, seizures, developmental delays, and behavioral problems (Bundey et al., 1994, pubmed:8050626; Burnside et al., 2011, pubmed:21359847). [from MIM:608636; 2018.11.06]
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). [From MIM:601623, 2017.03.18]
One to one (1 human to 1 Drosophila).
High-scoring ortholog of human UBE3A (1 Drosophila to 1 human); Dmel\Ube3a shares 41% identity and 57% similarity with the human gene.
