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

@article{Hamdan2011ExcessOD,
  title={Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability.},
  author={Fadi F. Hamdan and Julie Gauthier and Yoichi Araki and Daoyong Lin and Yuhki Yoshizawa and Kyohei Higashi and A-Reum Park and Dan Spiegelman and Sylvia Dobrzeniecka and Am{\'e}lie Piton and Hideyuki Tomitori and Hussein Daoud and Christine Massicotte and {\'E}douard Henrion and Ousmane Diallo and Masoud Shekarabi and Claude Marineau and Michael Israel Shevell and Bruno Maranda and Grant A Mitchell and Am{\'e}lie Nadeau and Guy D'anjou and Michel Vanasse and Myriam Srour and Ronald G. Lafreni{\'e}re and Pierre Drapeau and J-C. Lacaille and Eunjoon Kim and Jae-Ran Lee and Kazuei Igarashi and Richard L. Huganir and Guy A. Rouleau and Jacques L. Michaud},
  journal={American journal of human genetics},
  year={2011},
  volume={88 3},
  pages={
          306-16
        }
}

Figures and Tables from this paper

De Novo Mutations in Moderate or Severe Intellectual Disability
TLDR
It is concluded that DNMs represent a major cause of moderate or severe ID.
Rare mutations in N-methyl-D-aspartate glutamate receptors in autism spectrum disorders and schizophrenia
TLDR
The present results support the hypothesis that rare de novo mutations in GRIN2A or GRin2B can be associated with cases of sporadic SCZ or ASD, just as it has recently been described for the related neurodevelopmental disease intellectual disability.
De novo, heterozygous, loss‐of‐function mutations in SYNGAP1 cause a syndromic form of intellectual disability
TLDR
Clinical features of the individuals reported here show significant overlap with those associated with 6p21.3 microdeletions, confirming that haploinsufficiency for SYNGAP1 is responsible for both disorders.
Diagnostic exome sequencing in persons with severe intellectual disability.
TLDR
De novo mutations represent an important cause of intellectual disability; exome sequencing was used as an effective diagnostic strategy for their detection.
The Role of a Novel TRMT1 Gene Mutation and Rare GRM1 Gene Defect in Intellectual Disability in Two Azeri Families
TLDR
It is believed that this second Iranian family with a biallelic loss-of-function mutation in TRMT1 gene supports the idea that this gene likely has function in development of the disorder.
Mutations in SYNGAP1 Cause Intellectual Disability, Autism, and a Specific Form of Epilepsy by Inducing Haploinsufficiency
TLDR
This study confirms the involvement of SYNGAP1 in autism while providing novel insight into the epileptic manifestations associated with its disruption, and suggests that the de novo missense mutations, p.R579X, and possibly all the other truncating mutations in SYngAP1 result in a loss of its function.
A de novo loss-of-function GRIN2A mutation associated with childhood focal epilepsy and acquired epileptic aphasia
TLDR
Functional analyses reveal that the GluN2A(D731N) mutation decreases glutamate potency by over 3,000-fold, reduces amplitude of current response, shortens synaptic-like response time course, and decreases channel open probability, while enhancing sensitivity to negative allosteric modulators, including extracellular proton and zinc inhibition.
Dysfunction of SHANK2 and CHRNA7 in a patient with intellectual disability and language impairment supports genetic epistasis of the two loci
TLDR
Co‐occurrence of a de novo SHANK2 mutation and a CHRNA7 duplication in two reported patients with ASD and ID as well as in the patient with t(11;17;19), severe ID and behavior problems suggests convergence of these genes on a common synaptic pathway.
Novel homozygous missense variant of GRIN1 in two sibs with intellectual disability and autistic features without epilepsy.
TLDR
The present findings further expand the clinical spectrum of GRIN1 variants and support the existence of hypomorphic variants causing severe neurodevelopmental impairment with autosomal recessive inheritance.
...
...

References

SHOWING 1-10 OF 59 REFERENCES
Novel de novo SHANK3 mutation in autistic patients
  • J. Gauthier, D. Spiegelman, G. Rouleau
  • Biology
    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics
  • 2009
TLDR
The identification of two putative causative mutations are reported: one being a de novo deletion at an intronic donor splice site and one missense transmitted from an epileptic father, which further support the role of SHANK3 gene disruption in the etiology of ASD.
De novo STXBP1 mutations in mental retardation and nonsyndromic epilepsy
TLDR
The results suggest that STXBP1 disruption is associated with autosomal dominant mental retardation and nonsyndromic epilepsy.
De novo mutations in the gene encoding the synaptic scaffolding protein SHANK3 in patients ascertained for schizophrenia
TLDR
Two de novo mutations (R1117X and R536W) were identified in two families, one being found in three affected brothers, suggesting germline mosaicism.
Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation.
TLDR
The results indicate that SYNGAP1 disruption is a cause of autosomal dominant nonsyndromic mental retardation.
A de novo paradigm for mental retardation
TLDR
This work identified and validated unique non-synonymous de novo mutations in nine genes and identified six likely to be pathogenic based on gene function, evolutionary conservation and mutation impact that could explain the majority of all mental retardation cases in the population.
Direct measure of the de novo mutation rate in autism and schizophrenia cohorts.
Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes
TLDR
It is suggested that disturbances in the neuronal electrophysiological balance during development result in variable neurological phenotypes depending on which NR2 subunit of NMDA receptors is affected.
A defect in the ionotropic glutamate receptor 6 gene (GRIK2) is associated with autosomal recessive mental retardation.
TLDR
This finding provides the first proof that GLU(K6) is indispensable for higher brain functions in humans, and future studies of this and other ionotropic kainate receptors will shed more light on the pathophysiology of mental retardation.
Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders
TLDR
It is reported that a mutation of a single copy of SHANK3 on chromosome 22q13 can result in language and/or social communication disorders.
Mutations in ionotropic AMPA receptor 3 alter channel properties and are associated with moderate cognitive impairment in humans
TLDR
This study provides the genetic and functional evidence that mutant iGluR3 with altered kinetic properties is associated with moderate cognitive impairment in humans.
...
...