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General Information
Name
autism spectrum disorder, susceptibility to (postulated), TOP3B-related
FlyBase ID
FBhh0000847
OMIM
Overview

A number of variants in the human gene TOP3B have been tentatively associated with schizophrenia and autism. TOP3B encodes a dual DNA/RNA topoisomerase; it is postulated that its role in neurodevelopment is mediated by its interactions with mRNAs. There is a single orthologous gene in Drosophila, Top3β, for which RNAi-targeting constructs, alleles caused by insertional mutagenesis, and a loss-of-function mutation caused by imprecise excision of a TE insertion have been generated.

The human TOP3B gene has not been introduced into flies.

Assayed in larval neuromuscular junctions (NMJs), synapse formation is defective in a Top3β loss-of-function mutant. Assessment of the ability of Top3β transgenes with targeted mutational lesions to rescue the loss-of-function synapse phenotype indicates that both its RNA-binding activity and topoisomerase activity are required to promote synapse formation. A variant in the fly gene that is analogous to a human variant associated with autism is also unable to rescue the synapse phenotype. Variant(s) implicated in human disease tested (as analogous mutation in fly gene): C660R in the fly Top3β gene (corresponds to C666R in the human TOP3B gene).

Top3β has been shown to interact with genetically with Fmr1, the fly ortholog of the gene implicated in fragile X syndrome, FMR1. The Top3β protein has also been shown to physically interact with the Fmr1 protein (see below and in the corresponding gene reports). Synapse formation, as assayed in larval NMJs, is defective in both Top3β mutants and Fmr1 mutants. Symptoms overlapping those of autism spectrum disorder are frequently observed in individuals with fragile X syndrome.

[updated Jul. 2018 by FlyBase; FBrf0222196]

Disease Summary Information
Parent Disease Summary: autism spectrum disorder, susceptibility to
Symptoms and phenotype
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 (OMIM: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 OMIM:209850; 2017.03.18]
Specific Disease Summary: autism spectrum disorder, susceptibility to (postulated), TOP3B-related
OMIM report
Human gene(s) implicated
Symptoms and phenotype
Genetics
Cellular phenotype and pathology
Molecular information
TOP3B encodes a DNA topoisomerase, an enzyme that controls and alters the topologic states of DNA during transcription by releasing supercoiling and torsional tension. DNA topoisomerase catalyzes the transient breaking and rejoining of a single strand of DNA, which allows the strands to pass through one another. [Gene Cards, TOP3B; 2018.07.18]
TOP3B possesses dual activity for both RNA and DNA and appears to have an important role in RNA metabolism; it has been shown to be a component of cytosolic messenger ribonucleoproteins (mRNPs) and to be catalytically active on RNA (Stoll et al., 2013; pubmed:23912948).
External links
Disease synonyms
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
      Topoisomerase 3β (Top3β) encodes an RNA topoisomerase that participates in both transcription and translation. It promotes transcription by being recruited by the product of Tdrd3, an epigenetic reader recognizing dimethylarginine motifs in core histones. It contributes to translation by complexing with the product of Fmr1, an RNA-binding protein deficient in fragile X mental retardation syndrome. [Date last reviewed: 2019-03-14]
      Cellular component (GO)
      Gene Groups / Pathways
      Comments on ortholog(s)
      High-scoring ortholog of human TOP3B (1 Drosophila to 1 human). Dmel\Top3β shares 57% identity and 69% similarity with the human gene.
      Orthologs and Alignments from DRSC
      DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
      Synthetic Gene(s) Used (0)
      Summary of Physical Interactions (3 groups)
      protein-protein
      Interacting group
      Assay
      References
      anti tag coimmunoprecipitation, western blot, anti bait coimmunoprecipitation, Identification by mass spectrometry
      anti tag coimmunoprecipitation, Identification by mass spectrometry, western blot
      experimental knowledge based, anti bait coimmunoprecipitation, anti tag western blot, anti tag coimmunoprecipitation, Identification by mass spectrometry, western blot, coimmunoprecipitation
      Alleles Reported to Model Human Disease (Disease Ontology) (0 alleles)
      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 - genetic evidence
      P-element activity
      amorphic allele - genetic evidence
      P-element activity
      amorphic allele - genetic evidence
      P-element activity
      References (4)