An autism spectrum disorder mutation in Topoisomerase 3β causes accumulation of covalent mRNA intermediates by disrupting metal binding within the zinc finger domain.

Scientists studied a genetic change linked to autism that affects a protein called TOP3B. They found this change causes harmful protein clumps to build up in brain cells, which can damage neurons and interfere with how cells make proteins. This helps explain how certain genetic mutations might contribute to autism and other developmental conditions.

This laboratory study investigated how a specific genetic mutation (C666R) in the TOP3B gene, previously linked to autism, affects cellular function. Researchers used cell-based assays to demonstrate that this mutation disrupts the protein's normal metal-binding ability, causing accumulation of harmful protein-RNA complexes. The study showed these complexes can damage neurons and interfere with protein synthesis machinery (ribosomes). The findings provide new insights into how non-active site mutations in TOP3B contribute to neurological conditions including autism, schizophrenia, and intellectual disability, specifically through disruption of the zinc finger domain's metal coordination function.

This research advances understanding of how specific TOP3B mutations contribute to autism at the molecular level. While not immediately applicable to clinical practice, it may inform future therapeutic targets and genetic counseling for families with TOP3B-related autism mutations.

This is a laboratory-based mechanistic study using cell lines and does not directly demonstrate clinical outcomes in humans with autism. Sample sizes and specific methodological details are not provided in the abstract.

The loss and mutation of Topoisomerase 3β (TOP3B), the only known eukaryotic topoisomerase with the ability to catalyze RNA strand passage reactions, is linked to schizophrenia, autism, and intellectual disability. Uniquely, TOP3B primarily localizes to the cytoplasm and has been shown to regulate translation and stability of a subset of mRNA transcripts. Three neurological disease-linked de novo TOP3B point mutations outside of the active site have been identified but their impact on TOP3B activity in cells remains poorly understood. Upon establishing a new Neuro2A cell-based TOP3B activity assay, we provide genetic and biochemical evidence that the autism-linked C666R mutation causes accumulation of unresolved TOP3B•mRNA covalent intermediates by directly disrupting metal coordination via an atypical D1C3-type metal binding motif within the zinc finger domain.

Furthermore, we show that primary neurons are sensitive to TOP3B•mRNA covalent intermediates, including those formed by the C666R mutant TOP3B, and that such adducts are capable of causing ribosome collisions. Together, these data identify a previously underappreciated role of the zinc finger domain and how non-active site disease-linked mutations affect TOP3B activity and neuronal toxicity.