De Novo Truncating Mutation in Kinesin 17 Associated with Schizophrenia

Tarabeux, J., Champagne, N., Brustein, E., Hamdan, F.F., Gauthier, J., Lapointe, M., Maios, C., Piton, A., Spiegelman, D., Henrion, E., Team, S.T., Millet, B., Rapoport, J.L., Delisi, L.E., Joober, R., Fathalli, F., Fombonne, E., Mottron, L., Forget-Dubois, N., Boivin, M., Michaud, J.L., Lafrenière, R.G., Drapeau, P., Krebs, M.O., and Rouleau, G.A.
Biological psychiatry   68(7): 649-656 (Journal)
Registered Authors
Brustein, Edna, Drapeau, Pierre
De novo, KIF17, kinesin, NMDA, schizophrenia, synapse
MeSH Terms
  • Adult
  • Animals
  • Animals, Genetically Modified
  • Autistic Disorder/genetics
  • Cell Line, Transformed
  • Cohort Studies
  • DNA Mutational Analysis/methods
  • Female
  • Genetic Predisposition to Disease*
  • Genetic Testing/methods
  • Humans
  • Kinesins/genetics*
  • Larva
  • Male
  • Mutation/genetics*
  • Oligodeoxyribonucleotides, Antisense/pharmacology
  • RNA, Messenger/metabolism
  • Schizophrenia/genetics*
  • Transfection/methods
  • Zebrafish
20646681 Full text @ Biol. Psychiatry
BACKGROUND: Schizophrenia (SCZ) is one of the most disabling psychiatric disorders. It is thought to be due to a complex interplay between polygenic and various environmental risk factors, although recent reports on genomic copy number variations suggest that a fraction of the cases could result from variably penetrant de novo variants. The gene encoding the synaptic motor protein kinesin 17 (KIF17) involved in glutamatergic synapse is a candidate gene for SCZ. METHODS: As part of our Synapse to Disease project, we resequenced KIF17 in a cohort of individuals with sporadic SCZ (188 subjects). Additional populations included autism spectrum disorder (142 subjects), nonsyndromic mental retardation (95 subjects), and control subjects (568 subjects). Functional validation of the human mutation was done in developing zebrafish. RESULTS: Here we report the identification of a de novo nonsense truncating mutation in one patient with SCZ, in kinesin 17, a synaptic motor protein. No de novo or truncating KIF17 mutations were found in the additional samples. We further validated the pathogenic nature of this mutation by knocking down its expression in zebrafish embryos, which resulted in a developmental defect. CONCLUSIONS: Together our findings suggest that disruption of KIF17, although rare, could result in a schizophrenia phenotype and emphasize the possible involvement of rare de novo mutations in this disorder.
Genes / Markers
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Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes