Referenced in: none

Automatically associated channels: Cavγ2

Title: Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability.

Authors: Fadi F Hamdan, Julie Gauthier, Yoichi Araki, Da-Ting Lin, Yuhki Yoshizawa, Kyohei Higashi, A-Reum Park, Dan Spiegelman, Sylvia Dobrzeniecka, Amelie Piton, Hideyuki Tomitori, Hussein Daoud, Christine Massicotte, Edouard Henrion, Ousmane Diallo, , Masoud Shekarabi, Claude Marineau, Michael Shevell, Bruno Maranda, Grant Mitchell, Amélie Nadeau, Guy D'Anjou, Michel Vanasse, Myriam Srour, Ronald G Lafrenière, Pierre Drapeau, Jean Claude Lacaille, Eunjoon Kim, Jae-Ran Lee, Kazuei Igarashi, Richard L Huganir, Guy A Rouleau, Jacques L Michaud

Journal, date & volume: Am. J. Hum. Genet., 2011 Mar 11 , 88, 306-16

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/21376300

Abstract
Little is known about the genetics of nonsyndromic intellectual disability (NSID). We hypothesized that de novo mutations (DNMs) in synaptic genes explain an important fraction of sporadic NSID cases. In order to investigate this possibility, we sequenced 197 genes encoding glutamate receptors and a large subset of their known interacting proteins in 95 sporadic cases of NSID. We found 11 DNMs, including ten potentially deleterious mutations (three nonsense, two splicing, one frameshift, four missense) and one neutral mutation (silent) in eight different genes. Calculation of point-substitution DNM rates per functional and neutral site showed significant excess of functional DNMs compared to neutral ones. De novo truncating and/or splicing mutations in SYNGAP1, STXBP1, and SHANK3 were found in six patients and are likely to be pathogenic. De novo missense mutations were found in KIF1A, GRIN1, CACNG2, and EPB41L1. Functional studies showed that all these missense mutations affect protein function in cell culture systems, suggesting that they may be pathogenic. Sequencing these four genes in 50 additional sporadic cases of NSID identified a second DNM in GRIN1 (c.1679_1681dup/p.Ser560dup). This mutation also affects protein function, consistent with structural predictions. None of these mutations or any other DNMs were identified in these genes in 285 healthy controls. This study highlights the importance of the glutamate receptor complexes in NSID and further supports the role of DNMs in this disorder.