title: Deletion of TOP3β, a component of FMRP-containing mRNPs, contributes to neurodevelopmental disorders.
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.
authors.affiliation: Department of Biochemistry, University of Würzburg, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Stoll
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.|Institute for Molecular Medicine Finland (FIMM), Helsinki, Finland.|National Institute for Health and Welfare, Public Health Genomics Unit, Helsinki, Finland.
authors.forename: Olli P H
authors.initials: OPH
authors.lastname: Pietiläinen
authors.affiliation: Department of Biochemistry, University of Würzburg, Germany.
authors.forename: Bastian
authors.initials: B
authors.lastname: Linder
authors.affiliation: National Institute for Health and Welfare, Department of Mental Health and Substance Abuse Services, Helsinki, Finland.
authors.forename: Jaana
authors.initials: J
authors.lastname: Suvisaari
authors.affiliation: Department of Biochemistry, University of Würzburg, Germany.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Brosi
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), Helsinki, Finland.|National Institute for Health and Welfare, Department of Mental Health and Substance Abuse Services, Helsinki, Finland.
authors.forename: William
authors.initials: W
authors.lastname: Hennah
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), Helsinki, Finland.
authors.forename: Virpi
authors.initials: V
authors.lastname: Leppä
authors.affiliation: National Institute for Health and Welfare, Department of Mental Health and Substance Abuse Services, Helsinki, Finland.
authors.forename: Minna
authors.initials: M
authors.lastname: Torniainen
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.|Institute for Molecular Medicine Finland (FIMM), Helsinki, Finland.
authors.forename: Samuli
authors.initials: S
authors.lastname: Ripatti
authors.affiliation: Helsinki University Central Hospital, Department of Clinical Genetics, Helsinki, Finland.
authors.forename: Sirpa
authors.initials: S
authors.lastname: Ala-Mello
authors.affiliation: Pharma Research and Early Development, Roche Diagnostics GmbH, Penzberg, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Plöttner
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors.forename: Karola
authors.initials: K
authors.lastname: Rehnström
authors.affiliation: National Institute for Health and Welfare, Department of Mental Health and Substance Abuse Services, Helsinki, Finland.
authors.forename: Annamari
authors.initials: A
authors.lastname: Tuulio-Henriksson
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), Helsinki, Finland.|National Institute for Health and Welfare, Public Health Genomics Unit, Helsinki, Finland.
authors.forename: Teppo
authors.initials: T
authors.lastname: Varilo
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors.forename: Jonna
authors.initials: J
authors.lastname: Tallila
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), Helsinki, Finland.
authors.forename: Kati
authors.initials: K
authors.lastname: Kristiansson
authors.affiliation: Department of Psychiatry, Institute of Clinical Medicine, University of Oulu, Finland.
authors.forename: Matti
authors.initials: M
authors.lastname: Isohanni
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), Helsinki, Finland.|National Institute for Health and Welfare, Department of Mental Health and Substance Abuse Services, Helsinki, Finland.|Department of Public Health, University of Helsinki, Helsinki, Finland.
authors.forename: Jaakko
authors.initials: J
authors.lastname: Kaprio
authors.affiliation: National Institute for Health and Welfare, Chronic Disease Epidemiology and Prevention, Helsinki, Finland.|Department of General Practice and Primary Health Care, University of Helsinki, Finland.|Vasa Central Hospital, Finland.|Folkhälsan Research Centre, Helsinki, Finland.|Unit of General Practice, Helsinki University Central Hospital, Finland.
authors.forename: Johan G
authors.initials: JG
authors.lastname: Eriksson
authors.affiliation: Department of Clinical Physiology and Nuclear Medicine, University of Turku and Turku University Hospital, Turku, Finland.|Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku and Turku University Central Hospital, Turku, Finland.
authors.forename: Olli T
authors.initials: OT
authors.lastname: Raitakari
authors.affiliation: Department of Clinical Chemistry, University of Tampere and Tampere University Hospital, Finland.
authors.forename: Terho
authors.initials: T
authors.lastname: Lehtimäki
authors.affiliation: Department of Epidemiology and Biostatistics, Imperial College London, London, United Kingdom.|MRC-HPA Centre for Environment and Health, Imperial College London, London, United Kingdom.|National Institute of Health and Welfare, Oulu, Finland.|Institute of Health Sciences, University of Oulu, Oulu, Finland.
authors.forename: Marjo-Riitta
authors.initials: MR
authors.lastname: Jarvelin
authors.affiliation: National Institute for Health and Welfare, Department of Chronic Disease Prevention, Helsinki/Turku, Finland.
authors.forename: Veikko
authors.initials: V
authors.lastname: Salomaa
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Hurles
authors.affiliation: deCODE genetics, 101 Reykjavik, Iceland.
authors.forename: Hreinn
authors.initials: H
authors.lastname: Stefansson
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.|Institute for Molecular Medicine Finland (FIMM), Helsinki, Finland.|National Institute for Health and Welfare, Public Health Genomics Unit, Helsinki, Finland.|University of Helsinki, Department of Medical Genetics, Helsinki, Finland.
authors.forename: Leena
authors.initials: L
authors.lastname: Peltonen
authors.affiliation: Departments of Genetics, Psychiatry and Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Sullivan
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), Helsinki, Finland.|National Institute for Health and Welfare, Public Health Genomics Unit, Helsinki, Finland.|University of Helsinki and Helsinki University Central Hospital, Department of Psychiatry, Helsinki, Finland.
authors.forename: Tiina
authors.initials: T
authors.lastname: Paunio
authors.affiliation: National Institute for Health and Welfare, Department of Mental Health and Substance Abuse Services, Helsinki, Finland.|Helsinki University Central Hospital, Department of Clinical Genetics, Helsinki, Finland.
authors.forename: Jouko
authors.initials: J
authors.lastname: Lönnqvist
authors.affiliation: Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Daly
authors.affiliation: Department of Biochemistry, University of Würzburg, Germany.
authors.forename: Utz
authors.initials: U
authors.lastname: Fischer
authors.affiliation: Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, UCLA, Los Angeles, California, USA.
authors.forename: Nelson B
authors.initials: NB
authors.lastname: Freimer
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.|Institute for Molecular Medicine Finland (FIMM), Helsinki, Finland.|Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: Aarno
authors.initials: A
authors.lastname: Palotie
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D002872:Chromosome Deletion; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics; D003072:Cognition Disorders / Q000453:epidemiology / Q000235:genetics*; D015331:Cohort Studies; D004264:DNA Topoisomerases, Type I / Q000235:genetics*; D004062:DiGeorge Syndrome / Q000235:genetics*; D005192:Family Health; D005260:Female; D005387:Finland / Q000453:epidemiology; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D056726:Genetic Association Studies; D005838:Genotype; D057809:HEK293 Cells; D006306:Health Surveys; D006801:Humans; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D012261:Ribonucleoproteins / Q000235:genetics / Q000378:metabolism; D012559:Schizophrenia / Q000453:epidemiology / Q000235:genetics*; D017384:Sequence Deletion / Q000235:genetics*; D055815:Young Adult
chemical_list: D004264:DNA Topoisomerases, Type I; D051860:Fragile X Messenger Ribonucleoprotein 1; D011506:Proteins; D012261:Ribonucleoproteins; C532746:Tdrd3 protein, human; C026452:messenger ribonucleoprotein
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