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Cited by 350Genetics and Neurodevelopmental DisordersGenomics and Rare DiseasesDown syndrome and intellectual disability research

The DOI matches its Crossref record; 57 of the 58 references it cites were found in a registry or an index.

Excess of De Novo Deleterious Mutations in Genes Associated with Glutamatergic Systems in Nonsyndromic Intellectual Disability

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Hamdan, Fadi F., Gauthier, Julie, Araki, Yoichi, Lin, Da-Ting, Yoshizawa, Yuhki, Higashi, Kyohei, Park, A-Reum, Spiegelman, Dan, Dobrzeniecka, Sylvia, Piton, Amélie, Tomitori, Hideyuki, Daoud, Hussein, Massicotte, Christine, Henrion, Edouard, Diallo, Ousmane, Shekarabi, Masoud, Marineau, Claude, Shevell, Michael, Maranda, Bruno, Mitchell, Grant, Nadeau, Amélie, D'Anjou, Guy, Vanasse, Michel, Srour, Myriam, Lafrenière, Ronald G., Drapeau, Pierre, Lacaille, Jean Claude, Kim, Eunjoon, Lee, Jae-Ran, Igarashi, Kazuei, Huganir, Richard L., Rouleau, Guy A., Michaud, Jacques L.·2011·The American Journal of Human Genetics
DOI 10.1016/j.ajhg.2011.02.001PMC PMC3059427
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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.

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Authors
Hamdan, F. F., Gauthier, J., Araki, Y., Lin, D.-T., Yoshizawa, Y., Higashi, K., Park, A.-R., Spiegelman, D., Dobrzeniecka, S., Piton, A., Tomitori, H., Daoud, H., Massicotte, C., Henrion, E., Diallo, O., Shekarabi, M., Marineau, C., Shevell, M., Maranda, B., Mitchell, G., Nadeau, A., D'Anjou, G., Vanasse, M., Srour, M., Lafrenière, R. G., Drapeau, P., Lacaille, J. C., Kim, E., Lee, J.-R., Igarashi, K., Huganir, R. L., Rouleau, G. A., & Michaud, J. L.
Affiliations
  • Centre Hospitalier Universitaire Sainte-Justine (CA)
  • Centre Hospitalier de l’Université de Montréal (CA)
  • Howard Hughes Medical Institute (US)
  • Chiba University (JP)
  • Korea Research Institute of Bioscience and Biotechnology (KR)
  • Montreal Children's Hospital (CA)
  • Centre hospitalier de l'Université Laval (CA)
  • Université de Montréal (CA)
  • Korea Advanced Institute of Science and Technology (KR)
Corresponding author
Michaud, Jacques L.
ORCID
Venue
The American Journal of Human Genetics
Publisher
Elsevier BV
Published
2011-03
Volume
88
Issue
3
Pages
306-316
ISSN
0002-9297 (ISSN-L)
DOI
10.1016/j.ajhg.2011.02.001
PMC
PMC3059427
OpenAlex
W2033759150
Cited by
349
References
58
Citations by year
2026: 8 · 2025: 14 · 2024: 15 · 2023: 19 · 2022: 16 · 2021: 20 · 2020: 24 · 2019: 24 · 2018: 21 · 2017: 37 · 2016: 18 · 2015: 38 · 2014: 30 · 2013: 19 · 2012: 31
FWCI
18.96
Type
journal article
Language
en
Open access
Licence
Locations
  • The American Journal of Human Genetics (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • KRIBB Repository (submittedVersion)
Funders
  • Canadian Institutes of Health Research
  • Japan Society for the Promotion of Science (23390038)
  • National Institute of Neurological Disorders and Stroke (R01NS036715)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
Keywords
non-syndromic intellectual disability, de novo mutations, glutamate receptors, glutamatergic synapses, synaptic genes, missense mutations, truncating mutations, splicing mutation, SYNGAP1, STXBP1, SHANK3, KIF1A, GRIN1, protein function
MeSH terms
Animals, Base Sequence, Cytoskeletal Proteins, Female, Humans, Male, Membrane Proteins, Intellectual Disability, Mutation, Neuropeptides, Phenotype, Protein Binding, RNA Splicing, Subcellular Fractions, Syndrome, Calcium Channels, Receptors, N-Methyl-D-Aspartate, Kinesins, Receptors, AMPA, Glutamic Acid, Amino Acid Substitution, Mutation, Missense, Protein Transport, Rats, HEK293 Cells

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