1. Excess of De Novo Deleterious Mutations in Genes Associated with Glutamatergic Systems in Nonsyndromic Intellectual Disability
- Author
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Jacques L. Michaud, Ronald G. Lafrenière, Jae-Ran Lee, A-Reum Park, Michael Shevell, Hideyuki Tomitori, Yuhki Yoshizawa, Guy A. Rouleau, Michel Vanasse, Sylvia Dobrzeniecka, Jean-Claude Lacaille, Amélie Nadeau, Eunjoon Kim, Richard L. Huganir, Dan Spiegelman, Amélie Piton, Claude Marineau, Fadi F. Hamdan, Hussein Daoud, Guy D'Anjou, Pierre Drapeau, Bruno Maranda, Grant A. Mitchell, Kazuei Igarashi, Ousmane Diallo, Edouard Henrion, Masoud Shekarabi, Yoichi Araki, Christine Massicotte, Myriam Srour, Kyohei Higashi, Da Ting Lin, and Julie Gauthier
- Subjects
Male ,Kinesins ,SYNGAP1 ,medicine.disease_cause ,0302 clinical medicine ,Intellectual disability ,Missense mutation ,Genetics(clinical) ,Genetics (clinical) ,KIF1A ,Genetics ,0303 health sciences ,Mutation ,Syndrome ,3. Good health ,Protein Transport ,Phenotype ,Female ,Erratum ,Neutral mutation ,Protein Binding ,Subcellular Fractions ,RNA Splicing ,Mutation, Missense ,Glutamic Acid ,Biology ,Receptors, N-Methyl-D-Aspartate ,Article ,Frameshift mutation ,03 medical and health sciences ,Glutamatergic ,Intellectual Disability ,medicine ,Animals ,Humans ,Receptors, AMPA ,Gene ,030304 developmental biology ,Base Sequence ,Neuropeptides ,GRIN1 ,Membrane Proteins ,medicine.disease ,Human genetics ,030227 psychiatry ,Rats ,Cytoskeletal Proteins ,HEK293 Cells ,Amino Acid Substitution ,biology.protein ,Calcium Channels ,030217 neurology & neurosurgery - 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.
- Published
- 2011
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