Journal
NATURE NEUROSCIENCE
Volume 16, Issue 9, Pages 1228-U99Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nn.3484
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Funding
- Wellcome Trust [WT089062, WT098051]
- Academy of Finland [200923, 251704, 136635, 128504, 132071]
- Academy of Finland Center of Excellence in Complex Disease Genetics [213506, 129680]
- EuroHead project [LSM-CT-2004-504837]
- European Community's Seventh Framework Programme
- ENGAGE Consortium [HEALTH-F4-2007-201413]
- EU/SYNSYS-Synaptic Systems [242167]
- National Alliance for Research in Schizophrenia and Depression
- Sigrid Juselius Foundation
- Biomedicum Helsinki Foundation
- Jalmari and Rauha Ahokas Foundation
- Paivikki and Sakari Sohlberg Foundation
- Orion Farmos Research Foundation
- US National Institutes of Health [RL1MH083268, P30NS062691]
- DFG [FOR 855]
- Medical Research Council [G0801056B] Funding Source: researchfish
- Academy of Finland (AKA) [128504, 200923, 128504, 200923] Funding Source: Academy of Finland (AKA)
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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 TOP3 beta revealed that this topoisomerase was a component of cytosolic messenger ribonucleoproteins (mRNPs) and was catalytically active on RNA. The recruitment of TOP3 beta 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 TOP3 beta in mRNA metabolism and suggest that it is involved in neurodevelopmental disorders.
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