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, Amélie; Spiegelman, Dan; Henrion, Édouard; Millet, Bruno; Rapoport, Judith L.; DeLisi, Lynn E.; Joober, Ridha; Fathalli, Ferid; Fombonne, Éric; Mottron, Laurent; Forget‐Dubois, Nadine; Boivin, Michel; Michaud, Jacques L.; Lafrenière, Ronald G.; Drapeau, Pierre; Krebs, Marie‐Odile; Rouleau, Guy A.

doi:10.1016/j.biopsych.2010.04.018

Cited by 43 publications

(29 citation statements)

References 53 publications

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“…Consistent with this, presynaptic NMDARs have been suggested to play roles in epilepsy (Yang et al, 2007;Yang et al, 2006) and fetal alcohol spectrum disorders (Valenzuela et al, 2008). Mutations in NMDAR subunits are associated with autism, intellectual disability and epilepsy (Endele et al, 2010;Hamdan et al, 2011;O'Roak et al, 2011;O'Roak et al, 2012a;O'Roak et al, 2012b;Tarabeux et al, 2010;Yoo et al, 2012), and it will be interesting to determine whether presynaptic NMDARs are affected by these mutations and how presynaptic NMDARs might contribute to pathogenesis of these diseases.…”

Section: Presynaptic Nmdarsmentioning

confidence: 80%

Presynaptic NMDA receptors: dynamics and distribution in developing axons in vitro and in vivo

Gill

Droubi

Giovedì

et al. 2014

Journal of Cell Science

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BSTRACTDuring cortical development, N-methyl-D-aspartate (NMDA) receptors (NMDARs) facilitate presynaptic terminal formation, enhance neurotransmitter release and are required in presynaptic neurons for spike-timing-dependent long-term depression (tLTD). However, the extent to which NMDARs are found within cortical presynaptic terminals has remained controversial, and the subsynaptic localization and dynamics of axonal NMDARs are unknown. Here, using live confocal imaging and biochemical purification of presynaptic membranes, we provide strong evidence that NMDARs localize to presynaptic terminals in vitro and in vivo in a developmentally regulated manner. The NR1 and NR2B subunits (also known as GRIN1 and GRIN2B, respectively) were found within the active zone membrane, where they could respond to synaptic glutamate release. Surprisingly, NR1 also appeared in glutamatergic and GABAergic synaptic vesicles. During synaptogenesis, NR1 was mobile throughout axons -including growth cones and filopodia, structures that are involved in synaptogenesis. Upon synaptogenic contact, NMDA receptors were quickly recruited to terminals by neuroligin-1 signaling. Unlike dendrites, the trafficking and distribution of axonal NR1 were insensitive to activity changes, including NMDA exposure, local glutamate uncaging or action potential blockade. These results support the idea that presynaptic NMDARs play an early role in presynaptic development.

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Section: Presynaptic Nmdarsmentioning

confidence: 80%

Presynaptic NMDA receptors: dynamics and distribution in developing axons in vitro and in vivo

Gill

Droubi

Giovedì

et al. 2014

Journal of Cell Science

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“…The mutation resulted in truncation of the protein before the tail domain, the region important for interaction with the transport cargo (Goldstein et al, 2008). Similar truncations result in dominant negative motor proteins , explaining how such a mutation could result in deficits even when present in the heterozygous state (Tarabeux et al, 2010). Kinesin17 is an interesting candidate with regard to NDDs, as it was originally identified as a motor protein for NMDA receptor transport (Kayadjanian et al, 2007;Setou et al, 2000).…”

Section: Axonal and Dendritic Transport Of Synaptic Componentsmentioning

confidence: 97%

“…A nonsense mutation in Kinesin17 gene (KIF17) was found in a case of schizophrenia (Awadalla et al, 2010;Tarabeux et al, 2010). The mutation resulted in truncation of the protein before the tail domain, the region important for interaction with the transport cargo (Goldstein et al, 2008).…”

Section: Axonal and Dendritic Transport Of Synaptic Componentsmentioning

confidence: 99%

Synapse Assembly and Neurodevelopmental Disorders

Washbourne

2014

Neuropsychopharmacol

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“…This hypothesis did not receive much attention in genetic studies until recently, when high-throughput DNA sequencing of SCZ families provided direct evidence that affected offspring have excess DNMs across the genome [72,73] . Further studies of DNMs in individual genes [74,75] , a particular set of genes [76,77] , or the exome [78][79][80] , also provided evidence that DNMs are enriched in SCZ patients. Direct measurement also indicates that SCZ patients have a higher mutation rate [76] .…”

Section: De Novo Mutations In Sczmentioning

confidence: 95%

Genetic studies of schizophrenia: an update

et al. 2015

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Schizophrenia (SCZ) is a complex and heterogeneous mental disorder that affects about 1% of global population. In recent years, considerable progress has been made in genetic studies of SCZ. A number of common variants with small effects and rare variants with relatively larger effects have been identifi ed. These variants include risk loci identifi ed by genome-wide association studies, rare copy-number variants identifi ed by comparative genomic analyses, and de novo mutations identified by high-throughput DNA sequencing. Collectively, they contribute to the heterogeneity of the disease. In this review, we update recent discoveries in the fi eld of SCZ genetics, and outline the perspectives of future directions.

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De Novo Truncating Mutation in Kinesin 17 Associated with Schizophrenia

Cited by 43 publications

References 53 publications

Presynaptic NMDA receptors: dynamics and distribution in developing axons in vitro and in vivo

Presynaptic NMDA receptors: dynamics and distribution in developing axons in vitro and in vivo

Synapse Assembly and Neurodevelopmental Disorders

Genetic studies of schizophrenia: an update

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