Relevance to Autism

TOP2B was identified as an ASD candidate gene based on having a p-value < 0.001 following DeNovoWEST analysis of de novo variants in 16,877 ASD trios from the Simons Simplex Collection, the Autism Sequencing Consortium, the MSSNG cohort, and the SPARK cohort in Zhou et al., 2022; among the de novo variants observed in ASD cases in this analysis were three damaging de novo missense variants (defined as having a REVEL score > 0.5). The same de novo missense variant in TOP2B (c.187C>T;p.His63Tyr) was previously reported in two unrelated individuals presenting with developmental delay, intellectual disability, hypotonia, and autism spectrum disorder or autistic features, among other phenotypes (Lam et al., 2017; Hiraide et al., 2020). Knockdown of Top2b in neurons resulted in reduced expression of long (>200 kilobases) genes; many high-confidence ASD candidate genes are exceptionally long (King et al., 2013).

Molecular Function

This gene encodes a DNA topoisomerase, an enzyme that controls and alters the topologic states of DNA during transcription. This nuclear enzyme is involved in processes such as chromosome condensation, chromatid separation, and the relief of torsional stress that occurs during DNA transcription and replication. It catalyzes the transient breaking and rejoining of two strands of duplex DNA which allows the strands to pass through one another, thus altering the topology of DNA. Two forms of this enzyme exist as likely products of a gene duplication event. The gene encoding this form, beta, is localized to chromosome 3 and the alpha form is localized to chromosome 17. The gene encoding this enzyme functions as the target for several anticancer agents and a variety of mutations in this gene have been associated with the development of drug resistance. Reduced activity of this enzyme may also play a role in ataxia-telangiectasia.

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