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]
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]
The SFARI Gene autism database ( https:gene.sfari.org ) rates the gene-autism association for TOP3B as suggestive evidence (score 3). [2020.11.05]
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).
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]
One to one: 1 human to 1 Drosophila.
High-scoring ortholog of human TOP3B (1 Drosophila to 1 human). Dmel\Top3β shares 57% identity and 69% similarity with the human gene.
