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.


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


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

Supplementary concepts

  • Chromosome 22q11.2 Deletion Syndrome, Distal