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

Nature Neuroscience volume 16, pages 1228–1237 (2013)Cite this article

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Abstract

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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Figure 1: The frequency of neurodevelopmental disorders in Finland varies by region.
Figure 2: The 22q11.22 deletion covers about 240 kb, is present in homozygous form in individuals diagnosed with schizophrenia and/or cognitive deficits, and results in dose-dependent reduction in TOP3β.
Figure 3: TOP3β is part of a cytosolic, mRNP-associated protein complex that contains TDRD3 and FMRP.
Figure 4: TOP3β catalyzes RNA transesterification.
Figure 5: The TTF complex is present on early mRNPs that undergo the pioneer round of translation.
Figure 6: Formation of the TTF complex is essential for the co-recruitment of TOP3β and FMRP into mRNPs.

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Acknowledgements

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.

Author information

Author notes

  1. Leena Peltonen and Nelson B Freimer: Deceased.

  2. Georg Stoll, Olli P H Pietiläinen and Bastian Linder: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biochemistry, University of Würzburg, Würzburg, Germany

    Georg Stoll, Bastian Linder, Cornelia Brosi & Utz Fischer

  2. Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK

    Olli P H Pietiläinen, Samuli Ripatti, Karola Rehnström, Jonna Tallila, Matthew Hurles, Leena Peltonen & Aarno Palotie

  3. Institute for Molecular Medicine Finland, Helsinki, Finland

    Olli P H Pietiläinen, William Hennah, Virpi Leppä, Samuli Ripatti, Teppo Varilo, Kati Kristiansson, Jaakko Kaprio, Leena Peltonen, Tiina Paunio & Aarno Palotie

  4. National Institute for Health and Welfare, Public Health Genomics Unit, Helsinki, Finland

    Olli P H Pietiläinen, Teppo Varilo, Leena Peltonen & Tiina Paunio

  5. Department of Mental Health and Substance Abuse Services, National Institute for Health and Welfare, Helsinki, Finland

    Jaana Suvisaari, William Hennah, Minna Torniainen, Annamari Tuulio-Henriksson, Jaakko Kaprio & Jouko Lönnqvist

  6. Department of Clinical Genetics, Helsinki University Central Hospital, Helsinki, Finland

    Sirpa Ala-Mello & Jouko Lönnqvist

  7. Pharma Research and Early Development, Roche Diagnostics GmbH, Penzberg, Germany

    Oliver Plöttner

  8. Department of Psychiatry, Institute of Clinical Medicine, University of Oulu, Oulu, Finland

    Matti Isohanni

  9. Department of Public Health, University of Helsinki, Helsinki, Finland

    Jaakko Kaprio

  10. National Institute for Health and Welfare, Chronic Disease Epidemiology and Prevention, Helsinki, Finland

    Johan G Eriksson

  11. Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland

    Johan G Eriksson

  12. Vaasa Central Hospital, Vaasa, Finland

    Johan G Eriksson

  13. Folkhälsan Research Centre, Helsinki, Finland

    Johan G Eriksson

  14. Unit of General Practice, Helsinki University Central Hospital, Helsinki, Finland

    Johan G Eriksson

  15. Department of Clinical Physiology and Nuclear Medicine, University of Turku and Turku University Hospital, Turku, Finland

    Olli T Raitakari

  16. Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku and Turku University Central Hospital, Turku, Finland

    Olli T Raitakari

  17. Department of Clinical Chemistry, University of Tampere and Tampere University Hospital, Tampere, Finland

    Terho Lehtimäki

  18. Department of Epidemiology and Biostatistics, Imperial College London, London, UK

    Marjo-Riitta Jarvelin

  19. MRC-HPA Centre for Environment and Health, Imperial College London, London, UK

    Marjo-Riitta Jarvelin

  20. Department of Children, National Institute of Health and Welfare, Young People and Families, Oulu, Finland

    Marjo-Riitta Jarvelin

  21. Institute of Health Sciences, University of Oulu, Oulu, Finland

    Marjo-Riitta Jarvelin

  22. Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki/Turku, Finland

    Veikko Salomaa

  23. deCODE genetics, Reykjavik, Iceland

    Hreinn Stefansson

  24. Department of Medical Genetics, University of Helsinki, Helsinki, Finland

    Leena Peltonen

  25. Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

    Patrick F Sullivan

  26. Department of Psychiatry and Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

    Patrick F Sullivan

  27. Department of Psychiatry, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland

    Tiina Paunio

  28. Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA

    Mark J Daly

  29. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA

    Mark J Daly & Aarno Palotie

  30. Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, California, USA

    Nelson B Freimer

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Contributions

G.S., O.P.H.P., B.L., J.S., O.P., H.S., L.P., J.L., M.J.D., U.F., N.B.F. and A.P. participated in the study design and designed experiments. O.P.H.P., B.L., G.S., J.S., W.H., V.L., K.K., M.T., M.H., H.S., M.J.D., N.B.F., A.P., C.B., O.P., S.R., S.A.-M., K.R. and J.T. participated in data analysis and performed the experiments. O.P.H.P., J.S., M.J.D., N.B.F., A.P., G.S., B.L. and U.F. wrote the manuscript. All of the authors commented on the manuscript. J.S., A.T.-H., T.V., M.I., J.K., J.G.E., O.T.R., T.L., M.-R.J., V.S., P.F.S., T.P. and J.L. contributed to the collection of case and/or control samples.

Corresponding authors

Correspondence to Utz Fischer or Nelson B Freimer.

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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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