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]