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

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

Author information

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

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.

PMID:
23912948
PMCID:
PMC3986889
DOI:
10.1038/nn.3484
[Indexed for MEDLINE]
Free PMC Article
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