Deletion of TOP3β, a component of FMRP-containing mRNPs, contributes to neurodevelopmental disorders

Georg Stoll, Olli P H Pietiläinen, Bastian Linder, Jaana Suvisaari, Cornelia Brosi, William Hennah, Virpi Leppä, Minna Torniainen, Samuli Ripatti, Sirpa Ala-Mello, Oliver Plöttner, Karola Rehnström, Annamari Tuulio-Henriksson, Teppo Varilo, Jonna Tallila, Kati Kristiansson, Matti Isohanni, Jaakko Kaprio, Johan G Eriksson, Olli T Raitakari, Terho Lehtimäki, Marjo-Riitta Jarvelin, Veikko Salomaa, Matthew Hurles, Hreinn Stefansson, Leena Peltonen, Patrick F Sullivan, Tiina Paunio, Jouko Lönnqvist, Mark J Daly, Utz Fischer, Nelson B Freimer, Aarno Palotie

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.