De novo truncating mutation in Kinesin 17 associated with schizophrenia.
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.
Tarabeux
Julien
J
Department of Medicine, Center of Excellence in Neuromics of Université de Montréal, Centre Hospitalier de l'Université de Montreal Research Center, University of Montréal, Montreal, Quebec, Canada.
Champagne
Nathalie
N
Brustein
Edna
E
Hamdan
Fadi F
FF
Gauthier
Julie
J
Lapointe
Mathieu
M
Maios
Claudia
C
Piton
Amélie
A
Spiegelman
Dan
D
Henrion
Edouard
E
Millet
Bruno
B
Rapoport
Judith L
JL
Delisi
Lynn E
LE
Joober
Ridha
R
Fathalli
Ferid
F
Fombonne
Eric
E
Mottron
Laurent
L
Forget-Dubois
Nadine
N
Boivin
Michel
M
Michaud
Jacques L
JL
Lafrenière
Ronald G
RG
Drapeau
Pierre
P
Krebs
Marie-Odile
MO
Rouleau
Guy A
GA
D000328:Adult; D000818:Animals; D030801:Animals, Genetically Modified; D001321:Autistic Disorder / Q000235:genetics; D002461:Cell Line, Transformed; D015331:Cohort Studies; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods; D006801:Humans; D016547:Kinesins / Q000235:genetics*; D007814:Larva; D008297:Male; D009154:Mutation / Q000235:genetics*; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D012559:Schizophrenia / Q000235:genetics*; D014162:Transfection / Q000379:methods; D015027:Zebrafish
C485813:KIF17 protein, human; D020319:Oligodeoxyribonucleotides, Antisense; D012333:RNA, Messenger; D016547:Kinesins