De novo truncating mutation in kinesin 17 associated with schizophrenia

Julien Tarabeux, Nathalie Champagne, Edna Brustein, Fadi F. Hamdan, Julie Gauthier, Mathieu Lapointe, Claudia Maios, Amlie Piton, Dan Spiegelman, Édouard Henrion, Bruno Millet, Judith L. Rapoport, Lynn E. Delisi, Ridha Joober, Ferid Fathalli, Eric Fombonne, Laurent Mottron, Nadine Forget-Dubois, Michel Boivin, Jacques L. MichaudRonald G. Lafrenire, Pierre Drapeau, Marie Odile Krebs, Guy A. Rouleau

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)649-656
Number of pages8
JournalBiological Psychiatry
Volume68
Issue number7
DOIs
StatePublished - Oct 1 2010
Externally publishedYes

Fingerprint

Kinesin
Schizophrenia
Mutation
Zebrafish
Synapses
Nonsense Codon
Intellectual Disability
Genes
Psychiatry
Proteins
Embryonic Structures
Phenotype
Population

Keywords

  • De novo
  • KIF17
  • kinesin
  • NMDA
  • schizophrenia
  • synapse

ASJC Scopus subject areas

  • Biological Psychiatry

Cite this

Tarabeux, J., Champagne, N., Brustein, E., Hamdan, F. F., Gauthier, J., Lapointe, M., ... Rouleau, G. A. (2010). De novo truncating mutation in kinesin 17 associated with schizophrenia. Biological Psychiatry, 68(7), 649-656. https://doi.org/10.1016/j.biopsych.2010.04.018

De novo truncating mutation in kinesin 17 associated with schizophrenia. / Tarabeux, Julien; Champagne, Nathalie; Brustein, Edna; Hamdan, Fadi F.; Gauthier, Julie; Lapointe, Mathieu; Maios, Claudia; Piton, Amlie; Spiegelman, Dan; Henrion, Édouard; Millet, Bruno; Rapoport, Judith L.; Delisi, Lynn E.; Joober, Ridha; Fathalli, Ferid; Fombonne, Eric; Mottron, Laurent; Forget-Dubois, Nadine; Boivin, Michel; Michaud, Jacques L.; Lafrenire, Ronald G.; Drapeau, Pierre; Krebs, Marie Odile; Rouleau, Guy A.

In: Biological Psychiatry, Vol. 68, No. 7, 01.10.2010, p. 649-656.

Research output: Contribution to journalArticle

Tarabeux, J, Champagne, N, Brustein, E, Hamdan, FF, Gauthier, J, Lapointe, M, Maios, C, Piton, A, Spiegelman, D, Henrion, É, Millet, B, Rapoport, JL, Delisi, LE, Joober, R, Fathalli, F, Fombonne, E, Mottron, L, Forget-Dubois, N, Boivin, M, Michaud, JL, Lafrenire, RG, Drapeau, P, Krebs, MO & Rouleau, GA 2010, 'De novo truncating mutation in kinesin 17 associated with schizophrenia', Biological Psychiatry, vol. 68, no. 7, pp. 649-656. https://doi.org/10.1016/j.biopsych.2010.04.018
Tarabeux J, Champagne N, Brustein E, Hamdan FF, Gauthier J, Lapointe M et al. De novo truncating mutation in kinesin 17 associated with schizophrenia. Biological Psychiatry. 2010 Oct 1;68(7):649-656. https://doi.org/10.1016/j.biopsych.2010.04.018
Tarabeux, Julien ; Champagne, Nathalie ; Brustein, Edna ; Hamdan, Fadi F. ; Gauthier, Julie ; Lapointe, Mathieu ; Maios, Claudia ; Piton, Amlie ; Spiegelman, Dan ; Henrion, Édouard ; Millet, Bruno ; Rapoport, Judith L. ; Delisi, Lynn E. ; Joober, Ridha ; Fathalli, Ferid ; Fombonne, Eric ; Mottron, Laurent ; Forget-Dubois, Nadine ; Boivin, Michel ; Michaud, Jacques L. ; Lafrenire, Ronald G. ; Drapeau, Pierre ; Krebs, Marie Odile ; Rouleau, Guy A. / De novo truncating mutation in kinesin 17 associated with schizophrenia. In: Biological Psychiatry. 2010 ; Vol. 68, No. 7. pp. 649-656.
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AU - Tarabeux, Julien

AU - Champagne, Nathalie

AU - Brustein, Edna

AU - Hamdan, Fadi F.

AU - Gauthier, Julie

AU - Lapointe, Mathieu

AU - Maios, Claudia

AU - Piton, Amlie

AU - Spiegelman, Dan

AU - Henrion, Édouard

AU - Millet, Bruno

AU - Rapoport, Judith L.

AU - Delisi, Lynn E.

AU - Joober, Ridha

AU - Fathalli, Ferid

AU - Fombonne, Eric

AU - Mottron, Laurent

AU - Forget-Dubois, Nadine

AU - Boivin, Michel

AU - Michaud, Jacques L.

AU - Lafrenire, Ronald G.

AU - Drapeau, Pierre

AU - Krebs, Marie Odile

AU - Rouleau, Guy A.

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N2 - 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.

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