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

doi:10.1038/nn.3484

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

Nat Neurosci. 2013 Sep;16(9):1228-1237. doi: 10.1038/nn.3484. Epub 2013 Aug 4.

Authors

Georg Stoll^#¹, Olli P H Pietiläinen^#^{2

3

4}, Bastian Linder^#¹, Jaana Suvisaari⁵, Cornelia Brosi¹, William Hennah^{3

5}, Virpi Leppä³, Minna Torniainen⁵, Samuli Ripatti^{2

3}, Sirpa Ala-Mello⁶, Oliver Plöttner⁷, Karola Rehnström², Annamari Tuulio-Henriksson⁵, Teppo Varilo^{3

4}, Jonna Tallila², Kati Kristiansson³, Matti Isohanni⁸, Jaakko Kaprio^{3

5

9}, Johan G Eriksson^{10

11

12

13

14}, Olli T Raitakari^{15

16}, Terho Lehtimäki¹⁷, Marjo-Riitta Jarvelin^{18

19

20

21}, Veikko Salomaa²², Matthew Hurles², Hreinn Stefansson²³, Leena Peltonen^{2

3

4

24}, Patrick F Sullivan²⁵, Tiina Paunio^{3

4

26}, Jouko Lönnqvist^{5

6}, Mark J Daly^{27

28}, Utz Fischer¹, Nelson B Freimer²⁹, Aarno Palotie^{2

3

28}

Affiliations

¹ Department of Biochemistry, University of Würzburg, Germany.
² Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
³ Institute for Molecular Medicine Finland (FIMM), Helsinki, Finland.
⁴ National Institute for Health and Welfare, Public Health Genomics Unit, Helsinki, Finland.
⁵ National Institute for Health and Welfare, Department of Mental Health and Substance Abuse Services, Helsinki, Finland.
⁶ Helsinki University Central Hospital, Department of Clinical Genetics, Helsinki, Finland.
⁷ Pharma Research and Early Development, Roche Diagnostics GmbH, Penzberg, Germany.
⁸ Department of Psychiatry, Institute of Clinical Medicine, University of Oulu, Finland.
⁹ Department of Public Health, University of Helsinki, Helsinki, Finland.
¹⁰ National Institute for Health and Welfare, Chronic Disease Epidemiology and Prevention, Helsinki, Finland.
¹¹ Department of General Practice and Primary Health Care, University of Helsinki, Finland.
¹² Vasa Central Hospital, Finland.
¹³ Folkhälsan Research Centre, Helsinki, Finland.
¹⁴ Unit of General Practice, Helsinki University Central Hospital, Finland.
¹⁵ Department of Clinical Physiology and Nuclear Medicine, University of Turku and Turku University Hospital, Turku, Finland.
¹⁶ Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku and Turku University Central Hospital, Turku, Finland.
¹⁷ Department of Clinical Chemistry, University of Tampere and Tampere University Hospital, Finland.
¹⁸ Department of Epidemiology and Biostatistics, Imperial College London, London, United Kingdom.
¹⁹ MRC-HPA Centre for Environment and Health, Imperial College London, London, United Kingdom.
²⁰ National Institute of Health and Welfare, Oulu, Finland.
²¹ Institute of Health Sciences, University of Oulu, Oulu, Finland.
²² National Institute for Health and Welfare, Department of Chronic Disease Prevention, Helsinki/Turku, Finland.
²³ deCODE genetics, 101 Reykjavik, Iceland.
²⁴ University of Helsinki, Department of Medical Genetics, Helsinki, Finland.
²⁵ Departments of Genetics, Psychiatry and Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
²⁶ University of Helsinki and Helsinki University Central Hospital, Department of Psychiatry, Helsinki, Finland.
²⁷ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.
²⁸ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
²⁹ Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, UCLA, Los Angeles, California, USA.

^# Contributed equally.

PMID: 23912948
PMCID: PMC3986889
DOI: 10.1038/nn.3484

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Abnormalities, Multiple / genetics*
Adolescent
Adult
Aged
Chromosome Deletion
Chromosomes, Human, Pair 22 / genetics
Cognition Disorders / epidemiology
Cognition Disorders / genetics*
Cohort Studies
DNA Topoisomerases, Type I / genetics*
DiGeorge Syndrome / genetics*
Family Health
Female
Finland / epidemiology
Fragile X Mental Retardation Protein / genetics
Fragile X Mental Retardation Protein / metabolism
Gene Expression Profiling
Genetic Association Studies
Genotype
HEK293 Cells
Health Surveys
Humans
Male
Middle Aged
Models, Molecular
Proteins / genetics
Proteins / metabolism
Ribonucleoproteins / genetics
Ribonucleoproteins / metabolism
Schizophrenia / epidemiology
Schizophrenia / genetics*
Sequence Deletion / genetics*
Young Adult

Substances

Proteins
Ribonucleoproteins
Tdrd3 protein, human
messenger ribonucleoprotein
Fragile X Mental Retardation Protein
DNA Topoisomerases, Type I

Supplementary concepts

Chromosome 22q11.2 Deletion Syndrome, Distal

Abstract

Publication types

MeSH terms

Substances

Supplementary concepts

Grants and funding