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

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.

Pubmed ID: 21376300 RIS Download

Mesh terms: Amino Acid Substitution | Animals | Base Sequence | Calcium Channels | Cytoskeletal Proteins | Female | Glutamic Acid | HEK293 Cells | Humans | Intellectual Disability | Kinesin | Male | Membrane Proteins | Mutation | Mutation, Missense | Neuropeptides | Phenotype | Protein Binding | Protein Transport | RNA Splicing | Rats | Receptors, AMPA | Receptors, N-Methyl-D-Aspartate | Subcellular Fractions | Syndrome

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Associated grants

  • Agency: Canadian Institutes of Health Research, Id:

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UniProt

Collection of data of protein sequence and functional information. UniProt databases are UniProt Knowledgebase (UniProtKB), UniProt Reference Clusters (UniRef), and UniProt Archive (UniParc).

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Genes to Cognition Online

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PANTHER

Classification system that classifies genes by their functions, using published scientific experimental evidence and evolutionary relationships to predict function even in the absence of direct experimental evidence. Proteins are classified by expert biologists according to: * Gene families and subfamilies, including annotated phylogenetic trees * Gene Ontology classes: molecular function, biological process, cellular component * PANTHER Protein Classes * Pathways, including diagrams The PANTHER Classifications are the result of human curation as well as sophisticated bioinformatics algorithms. Details of the methods can be found in (Thomas et al., Genome Research 2003; Mi et al. NAR 2005). Version 8.1 contains 7729 protein families, each with a phylogenetic tree relating modern-day genes in 48 organisms.) PANTHER contains the complete sets of protein coding genes for 48 organisms, obtained from definitive sources. PANTHER uses the Gene Ontology for classifications by molecular function, biological process and cellular component. The PANTHER Protein Class ontology was adapted from the PANTHER/X molecular function ontology, and includes commonly used classes of protein functions, many of which are not covered by GO molecular function. You may download the classes and relationship information. PANTHER uses only a subset of GO terms (GO slim) to facilitate browsing. You may download the PANTHER GO slim. You may Score proteins against the PANTHER HMM library and download PANTHER tools and data. PANTHER Pathway consists of over 176, primarily signaling, pathways, each with subfamilies and protein sequences mapped to individual pathway components. Pathways are drawn using CellDesigner software, capturing molecular level events in both signaling and metabolic pathways, and can be exported in SBML format. The SBGN view of the diagram can also be exported. Pathway diagrams are interactive and include tools for visualizing gene expression data in the context of the diagrams.

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UCSC Genome Browser

A collection of genomes which include reference sequences and working draft assemblies, as well as a variety of tools to explore these sequences. The Genome Browser zooms and scrolls over chromosomes, showing the work of annotators worldwide. The Gene Sorter shows expression, homology and other information on groups of genes that can be related in many ways. Blat quickly maps your sequence to the genome. The Table Browser provides access to the underlying database. VisiGene lets you browse through a large collection of in situ mouse and frog images to examine expression patterns. Genome Graphs allows you to upload and display genome-wide data sets. Also provided is a portal to the Encyclopedia of DNA Elements (ENCODE) and Neandertal projects.

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