Rare mutations in N-methyl-D-aspartate glutamate receptors in autism spectrum disorders and schizophrenia

abstract: ...Pharmacological, genetic and expression studies implicate N-methyl-D-aspartate (NMDA) receptor hypofunction in schizophrenia (SCZ). Similarly, several lines of evidence suggest that autism spectrum disorders (ASD) could be due to an imbalance between excitatory and inhibitory neurotransmission. As part of a project aimed at exploring rare and/or de novo mutations in neurodevelopmental disorders, we have sequenced the seven genes encoding for NMDA receptor subunits (NMDARs) in a large cohort of individuals affected with SCZ or ASD ( n =429 and 428, respectively), parents of these subjects and controls ( n =568). Here, we identified two de novo mutations in patients with sporadic SCZ in GRIN2A and one de novo mutation in GRIN2B in a patient with ASD. Truncating mutations in GRIN2C , GRIN3A and GRIN3B were identified in both subjects and controls, but no truncating mutations were found in the GRIN1 , GRIN2A , GRIN2B and GRIN2D genes, both in patients and controls, suggesting that these subunits are critical for neurodevelopment. The present results support the hypothesis that rare de novo mutations in GRIN2A or GRIN2B can be associated with cases of sporadic SCZ or ASD, just as it has recently been described for the related neurodevelopmental disease intellectual disability. The influence of genetic variants appears different, depending on NMDAR subunits. Functional compensation could occur to counteract the loss of one allele in GRIN2C and GRIN3 family genes, whereas GRIN1, GRIN2A , GRIN2B and GRIN2D appear instrumental to normal brain development and function.

... ( n =429 and 428, respectively), parents of these subjects and controls ( n =568). Here, we identified two de novo mutations in patients with sporadic SCZ in GRIN2A and one de novo mutation in GRIN2B in a patient with ASD. Truncating mutations in GRIN2C , GRIN3A and GRIN3B were identified in both subjects and controls, but no truncating mutations were found in the GRIN1 , GRIN2A , GRIN2B and GRIN2D genes, both in patients and controls, suggesting that these subunits are critical for

... synapses: SHANK3 , encoding a scaffolding protein at the excitatory synapse and KIF17 encoding a synaptic motor protein, involved in the transport of NMDA receptor 2B (NR2B) to the synapse. 48 As part of the Synapse to Disease Project, in which we screened 600 synaptic genes, we screened all exons of the seven NMDARs in 571 individuals, including 429 patients with SCZ and 142 patients with ASD. We also screened all exons of the NMDARs (except for GRIN3B and GRIN1 ) in 283 healthy controls. Further, we screened additional cohort of ASD patients ( n =286) for GRIN2B , GRIN2C and GRIN3B , and additional cohort of controls from the general population ( n =285) for GRIN2C and GRIN3A . For GRIN1 , we screened only this general population cohort of controls. Finally, we determined transmission of all unique variants, identified in only one individual, by sequencing parents of the carrier (292 SCZ and 404 ASD patients, with 2 parents available for screening). We here report the identification of de novo mutations in patients with SCZ in the GRIN2A gene and in a patient with ASD in the GRIN2B gene. Also, we report the absence of truncating mutation in the GRIN1 , GRIN2A , GRIN2B and GRIN2D genes in patients or controls, whereas we identified truncating mutations in the GRIN2C , GRIN3A and GRIN3B genes in patients and controls. Methods Subject collection SCZ cohort Subjects with SCZ were selected from over 1000 families ascertained for genetic studies, for which DNA samples were available. The screened

... variants in GRIN2B , GRIN2C and GRIN3B. Briefly, all subjects were diagnosed using DSM-IV or DSM-IIIR criteria, and depending of the recruitment site, Autism Diagnostic Interview-Revised and the Autism Diagnostic Observation Schedule were used. In addition, the Autism Screening Questionnaire was also completed for all subjects. We excluded patients with an estimated mental age <18 months, a diagnosis of Rett syndrome or childhood disintegrative disorder, and patients with evidence of any psychiatric

...-negative controls. These included 283 adult subjects (131 males; 152 females), 225 of whom were of European origin and 58 were non-Europeans (Tunisian). The second group of controls comprised 285 subjects from a general population control group of mainly French Canadian origin, for whom we also had parental DNA (Quebec Newborn Twin Study; 150 males, 135 females). 55 We have systematically sequenced all exons of the seven NMDAR genes (except for GRIN3B and GRIN1 ) in the cohort of healthy volunteer

... sequenced the coding region and the splice junction of GRIN1 (chr9: 140,033,609140,063,207, hg19 assembly), GRIN2A (chr16: 9,847,26710,276,263), GRIN2B (chr12: 13,714,41014,133,022), GRIN2C (chr17: 72,838,16872,856,007), GRIN2D (chr19: 48,898,13248,948,187), GRIN3A (chr9: 104,331,635104,500,862). GRIN3B (chr19: 1,000,4371,009,723) was sequenced only in patients. The detailed descriptions of the samples screened for each NMDAR gene are mentioned in Table 1 . Primers were designed using the ExonPrimer

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Gene: GRIN3B - glutamate receptor, ionotropic, N-methyl-D-aspartate 3B - (NCBI)

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