title: GRIN3B missense mutation as an inherited risk factor for schizophrenia: whole-exome sequencing in a family with a familiar history of psychotic disorders.
abstract: Glutamate is the most important excitatory neurotransmitter in the brain. The N-methyl-D-aspartate (NMDA) receptor is a glutamate-gated ionotropic cation channel that is composed of several subunits and modulated by a glycine binding site. Many forms of synaptic plasticity depend on the influx of calcium ions through NMDA receptors, and NMDA receptor dysfunction has been linked to a number of neuropsychiatric disorders, including schizophrenia. Whole-exome sequencing was performed in a family with a strong history of psychotic disorders over three generations. We used an iterative strategy to obtain condense and meaningful variants. In this highly affected family, we found a frameshift mutation (rs10666583) in the GRIN3B gene, which codes for the GluN3B subunit of the NMDA receptor in all family members with a psychotic disorder, but not in the healthy relatives. Matsuno et al., also reported this null variant as a risk factor for schizophrenia in 2015. In a broader sample of 22 patients with psychosis, the allele frequency of the rs10666583 mutation variant was increased compared to those of healthy population samples and unaffected relatives. Compared to the 1000 Genomes Project population, we found a significant increase of this variant with a large effect size among patients. The amino acid shift degrades the S1/S2 glycine binding domain of the dominant modulatory GluN3B subunit of the NMDA receptor, which subsequently affects the permeability of the channel pore to calcium ions. A decreased glycine affinity for the GluN3B subunit might cause impaired functional capability of the NMDA receptor and could be an important risk factor for the pathogenesis of psychotic disorders.
authors.affiliation: Department of Psychiatry and Psychotherapy,University Medical Center,Albert-Ludwigs University,Hauptstr. 5,79104 Freiburg,Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Hornig
authors.affiliation: Bioinformatics Group,Department of Computer Science,University of Freiburg,Georges-Koehler-Allee 106,Freiburg 79110,Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: Grüning
authors.affiliation: Bioinformatics Group,Department of Computer Science,University of Freiburg,Georges-Koehler-Allee 106,Freiburg 79110,Germany.
authors.forename: Kousik
authors.initials: K
authors.lastname: Kundu
authors.affiliation: Bioinformatics Group,Department of Computer Science,University of Freiburg,Georges-Koehler-Allee 106,Freiburg 79110,Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Houwaart
authors.affiliation: Bioinformatics Group,Department of Computer Science,University of Freiburg,Georges-Koehler-Allee 106,Freiburg 79110,Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Backofen
authors.affiliation: Department of Psychiatry and Psychotherapy,University Medical Center,Albert-Ludwigs University,Hauptstr. 5,79104 Freiburg,Germany.
authors.forename: Knut
authors.initials: K
authors.lastname: Biber
authors.affiliation: Department of Psychiatry and Psychotherapy,University Medical Center,Albert-Ludwigs University,Hauptstr. 5,79104 Freiburg,Germany.
authors.forename: Claus
authors.initials: C
authors.lastname: Normann
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D059472:Exome / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D011618:Psychotic Disorders / Q000235:genetics*; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics*; D012307:Risk Factors; D012559:Schizophrenia / Q000235:genetics*; D055815:Young Adult
chemical_list: C501155:NR3B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate