Implicating particular genes in the generation of complex brain and behavior phenotypes requires multiple lines of evidence. The rarity of most high-impact genetic variants typically precludes the possibility of accruing statistical evidence that they are associated with a given trait. We found that the enrichment of a rare chromosome 22q11.22 deletion in a recently expanded Northern Finnish sub-isolate enabled the detection of association between TOP3B and both schizophrenia and cognitive impairment. Biochemical analysis of TOP3β revealed that this topoisomerase was a component of cytosolic messenger ribonucleoproteins (mRNPs) and was catalytically active on RNA. The recruitment of TOP3β to mRNPs was independent of RNA cis-elements and was coupled to the co-recruitment of FMRP, the disease gene product in fragile X mental retardation syndrome. Our results indicate a previously unknown role for TOP3β in mRNA metabolism and suggest that it is involved in neurodevelopmental disorders.
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We thank R. Durbin for providing genotype data from the 173 individuals who constitute the sub-isolate population sample, C. Sabatti for helpful suggestions, and B. Laggerbauer and A. Hirmer for critically reading the manuscript. This work was supported by The Wellcome Trust (grant numbers WT089062 and WT098051 to A.P.), the Academy of Finland (project grants 200923 and 251704 to A.P., 136635 to V.S., 128504 to W.H., and 132071 to M.I.), the Academy of Finland Center of Excellence in Complex Disease Genetics (grant numbers 213506 and 129680 to A.P. and J.K.), the EuroHead project (LSM-CT- 2004-504837), the European Community's Seventh Framework Programme (FP7/2007-2013), the ENGAGE Consortium (grant agreement HEALTH-F4-2007-201413), EU/SYNSYS-Synaptic Systems (grant number 242167 to A.P.), the National Alliance for Research in Schizophrenia and Depression, Sigrid Juselius Foundation (to J.L. and A.P.), the Biomedicum Helsinki Foundation (to O.P.H.P.), the Jalmari and Rauha Ahokas Foundation (to O.P.H.P.), the Päivikki and Sakari Sohlberg Foundation (to A.P.), the Orion Farmos Research Foundation (to W.H.), grants RL1MH083268 and P30NS062691 from the US National Institutes of Health (to N.B.F.), and grants of the RVZ-network and the DFG (FOR 855) to U.F.
The authors declare no competing financial interests.
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Stoll, G., Pietiläinen, O., Linder, B. et al. Deletion of TOP3β, a component of FMRP-containing mRNPs, contributes to neurodevelopmental disorders. Nat Neurosci 16, 1228–1237 (2013). https://doi.org/10.1038/nn.3484
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