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Relevance to Autism

Studies have found genetic association between the GRIK2 gene and autism. Positive associations have been found in the Chinese Han population among others. No association between GRIK2 and autism was found in an Indian population sample, however.

Molecular Function

Glutamate receptors are the predominant excitatory neurotransmitter receptors in the mammalian brain and are activated in a variety of normal neurophysiologic processes. This gene product belongs to the kainate family of glutamate receptors, which are composed of four subunits and function as ligand-activated ion channels. The subunit encoded by this gene is subject to RNA editing at multiple sites within the first and second transmembrane domains, which is thought to alter the structure and function of the receptor complex. Mutations in this gene have been associated with autosomal recessive cognitive disability.

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Linkage and association of the glutamate receptor 6 gene with autism.
ASD
Positive Association
Linkage and candidate gene studies of autism spectrum disorders in European populations.
ASD
Positive Association
Family-based association study between autism and glutamate receptor 6 gene in Chinese Han trios.
ASD
Positive Association
Phenome-wide association study (PheWAS) in EMR-linked pediatric cohorts, genetically links PLCL1 to speech language development and IL5-IL13 to Eos...
ASD
Positive Association
A candidate gene association study further corroborates involvement of contactin genes in autism.
ASD
Negative Association
Glutamate receptor 6 gene (GluR6 or GRIK2) polymorphisms in the Indian population: a genetic association study on autism spectrum disorder.
ASD
Support
Integrating de novo and inherited variants in 42
ASD
Support
Expanding the spectrum of Grik2 mutations: intellectual disability, behavioural disorder, epilepsy and dystonia.
Epilepsy, ID
Support
Mutational Landscape of Autism Spectrum Disorder Brain Tissue
ASD
Support
A discovery resource of rare copy number variations in individuals with autism spectrum disorder.
ASD
Support
Damaging coding variants within kainate receptor channel genes are enriched in individuals with schizophrenia, autism and intellectual disabilities.
SCZ
Support
Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy.
Epilepsy
Support
Both rare and common genetic variants contribute to autism in the Faroe Islands.
ASD
Support
Leveraging blood serotonin as an endophenotype to identify de novo and rare variants involved in autism.
ASD
Support
A gain-of-function mutation in the GRIK2 gene causes neurodevelopmental deficits.
DD, ID
Microcephaly, hypotonia, ataxia, stereotypic behav
Support
Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior.
ASD
Highly Cited
Altered synaptic physiology and reduced susceptibility to kainate-induced seizures in GluR6-deficient mice.
Highly Cited
Genotypes at the GluR6 kainate receptor locus are associated with variation in the age of onset of Huntington disease.
Recent Recommendation
Clustered mutations in the GRIK2 kainate receptor subunit gene underlie diverse neurodevelopmental disorders
DD
ASD, ID, epilepsy/seizures
Recent Recommendation
Integrated systems analysis reveals a molecular network underlying autism spectrum disorders.
ASD
Recent Recommendation
Interdomain interactions in AMPA and kainate receptors regulate affinity for glutamate.
Recent Recommendation
Glutamate receptor agonist kainate enhances primary dendrite number and length from immature mouse cortical neurons in vitro.
Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN109R001 
 missense_variant 
 c.1261C>T 
 p.Pro421Ser 
 Unknown 
  
 Unknown 
 GEN109R002 
 missense_variant 
 C>A 
 p.Asn654Lys 
 Unknown 
  
 Unknown 
 GEN109R003 
 copy_number_loss 
  
  
 Unknown 
  
 Unknown 
 GEN109R004 
 copy_number_gain 
  
  
 Unknown 
  
 Unknown 
 GEN109R005a 
 stop_gained 
 c.592C>T 
 p.Arg198Ter 
 Familial 
 Both parents 
 Multiplex 
 GEN109R006 
 nonsynonymous_variant 
  
  
 Unknown 
  
 Unknown 
 GEN109R007 
 intergenic_variant 
 insA 
  
  
  
 Unknown 
 GEN109R008 
 missense_variant 
 c.1969G>A 
 p.Ala657Thr 
 De novo 
  
  
 GEN109R009 
 missense_variant 
 c.2156A>G 
 p.Lys719Arg 
 De novo 
  
 Simplex 
 GEN109R010 
 stop_gained 
 c.2663T>G 
 p.Leu888Ter 
 Familial 
 Maternal 
 Simplex 
 GEN109R011 
 stop_gained 
 c.2663T>G 
 p.Leu888Ter 
 Familial 
 Paternal 
 Simplex 
 GEN109R012 
 missense_variant 
  
 p.Lys525Glu 
 Unknown 
  
 Unknown 
 GEN109R013 
 missense_variant 
 c.1969G>A 
 p.Ala657Thr 
 De novo 
  
  
 GEN109R014 
 missense_variant 
 c.1969G>A 
 p.Ala657Thr 
 De novo 
  
  
 GEN109R015 
 missense_variant 
 c.1969G>A 
 p.Ala657Thr 
 De novo 
  
  
 GEN109R016 
 missense_variant 
 c.1969G>A 
 p.Ala657Thr 
 De novo 
  
  
 GEN109R017 
 missense_variant 
 c.1969G>A 
 p.Ala657Thr 
 De novo 
  
  
 GEN109R018 
 missense_variant 
 c.1979C>A 
 p.Thr660Lys 
 De novo 
  
  
 GEN109R019 
 missense_variant 
 c.1979C>A 
 p.Thr660Lys 
 De novo 
  
  
 GEN109R020 
 missense_variant 
 c.1979C>A 
 p.Thr660Lys 
 De novo 
  
  
 GEN109R021 
 missense_variant 
 c.1979C>G 
 p.Thr660Arg 
 De novo 
  
  
 GEN109R022 
 missense_variant 
 c.1979C>G 
 p.Thr660Arg 
 De novo 
  
  
 GEN109R023 
 missense_variant 
 c.2003T>C 
 p.Ile668Thr 
 De novo 
  
  
 GEN109R024 
 intron_variant 
 c.2563-2515C>T 
  
 Unknown 
  
  
 GEN109R025 
 stop_gained 
 c.493C>T 
 p.Gln165Ter 
 De novo 
  
  
 GEN109R026 
 missense_variant 
 c.851C>T 
 p.Thr284Ile 
 De novo 
  
  
 GEN109R027 
 stop_gained 
 c.898C>T 
 p.Arg300Ter 
 De novo 
  
  
 GEN109R028 
 missense_variant 
 c.2156A>G 
 p.Lys719Arg 
 De novo 
  
  
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
6
Deletion
 1
 
6
Deletion
 5
 
6
Deletion
 1
 
6
Deletion
 1
 
6
Deletion
 1
 
6
Deletion-Duplication
 16
 
6
Deletion
 2
 

Model Summary

Mutation in a gene linked to ID in the human may lead to a transiet reduction of synaptic strength during postnatal development, impacting on the proper formation of neural circuits linked to memory.

References

Type
Title
Author, Year
Primary
Deficits in morphofunctional maturation of hippocampal mossy fiber synapses in a mouse model of intellectual disability.
Additional
Complete Disruption of the Kainate Receptor Gene Family Results in Corticostriatal Dysfunction in Mice.
Model Type: Genetic
Model Genotype: Homozygous
Mutation: Homologous recombination mediated deletion of 0.7 kb including exon coding for MD2 of Grik2 gene.
Allele Type: Targeted (Knock Out)
Strain of Origin: Not specified
Genetic Background: C57BL6/SV129 x FVB
ES Cell Line: Not specified
Mutant ES Cell Line: Not Specified
Model Source: Not Specified
Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Synaptic morphology1
Abnormal
 Confocal microscopy
 P9, p14
Synaptic morphology1
Abnormal
 Confocal microscopy
 P6-p21
Dendritic architecture: spine density1
Abnormal
 Confocal microscopy
 P14, p21
Synaptic transmission1
Abnormal
 Whole-cell patch clamp
 P6-p21
Synaptic neuroreceptor ratio (nmdar/ampar) dependent transmission1
Abnormal
 Whole-cell patch clamp
 P6-p21
Presynaptic function: paired-pulse facilitation1
Abnormal
 Whole-cell patch clamp
 P6-p21
Neurotransmitter release: quantal parameters1
Abnormal
 Multiple-probability fluctuation analysis
 P9
Protein expression level evidence1
Decreased
 Immunohistochemistry
 P9
Protein expression level evidence1
Decreased
 Immunohistochemistry
 P9
 Not Reported: Circadian sleep/wake cycle, Communications, Developmental profile, Emotion, Immune response, Learning & memory, Maternal behavior, Motor phenotype, Physiological parameters, Repetitive behavior, Seizure, Sensory, Social behavior


Interactor Symbol Interactor Name Interactor Organism Entrez ID Uniprot ID Interaction Type Evidence Reference
C1ql2 complement component 1, q subcomponent-like 2 226359 Q8CFR0 Cell surface binding assay; Surface plasmon resonance (SPR); Co-localization
Matsuda K , et al. 2016
C1ql3 C1q-like 3 227580 B0LXL6 Cell surface binding assay; Surface plasmon resonance (SPR); Co-localization
Matsuda K , et al. 2016
CASK calcium/calmodulin-dependent serine protein kinase (MAGUK family) 12361 O70589 IP/WB; GST
Coussen F , et al. 2002
CTNNB1 catenin (cadherin associated protein), beta 1 12387 Q02248 IP/WB; GST
Coussen F , et al. 2002
CTNND1 catenin (cadherin associated protein), delta 1 12388 P30999 IP/WB
Coussen F , et al. 2002
DLG1 discs, large homolog 1 (Drosophila) 25252 Q62696 IP/WB
Garcia EP , et al. 1998
DLG3 discs, large homolog 3 (Drosophila) 58948 Q62936 IP/WB
Garcia EP , et al. 1998
DLG4 Postsynaptic density protein 95 13385 Q62108 IP; LC-MS/MS
Frank RA , et al. 2016
DLG4 discs, large homolog 4 (Drosophila) 29495 P31016 IP/WB; GST
Garcia EP , et al. 1998
FMR1 fragile X mental retardation 1 2332 G8JLE9 PAR-CLIP
Ascano M Jr , et al. 2012
GRIA1 glutamate receptor, ionotropic, AMPA 1 2890 P42261 IP/WB
Leuschner WD and Hoch W 1999
GRIA2 glutamate receptor, ionotropic, AMPA 2 2891 P42262 IP/WB
Wenthold RJ , et al. 1994
GRID2 glutamate receptor, ionotropic, delta 2 2895 O43424 IP/WB
Kohda K , et al. 2003
GRIK2 glutamate receptor, ionotropic, kainate 2 54257 P42260 X-ray crystallography; Sedimentation equilibrium analysis
Kumar J , et al. 2011
GRIK4 glutamate receptor, ionotropic, kainate 4 110637 Q8BMF5 IP/WB
Darstein M , et al. 2003
GRIK5 glutamate receptor, ionotropic, kainate 5 (gamma 2) 14809 Q61626 IP/WB
Darstein M , et al. 2003
Grik5 glutamate receptor, ionotropic, kainate 5 (gamma 2) 14809 Q61626 IP/WB
Straub C , et al. 2016
GRIP1 glutamate receptor interacting protein 1 74053 Q925T6 GST
Hirbec H , et al. 2002
KLHL17 kelch-like 17 (Drosophila) 246757 Q8K430 Y2H; IP/WB
Salinas GD , et al. 2006
KLHL24 kelch-like 24 (Drosophila) 303803 Q56A24 Y2H; IP/WB
Laezza F , et al. 2007
LIN7A lin-7 homolog A (C. elegans) 108030 Q8JZS0 IP/WB
Coussen F , et al. 2002
Neto1 neuropilin (NRP) and tolloid (TLL)-like 1 246317 Q8R4I7 IP/WB
Straub C , et al. 2016
Neto2 neuropilin (NRP) and tolloid (TLL)-like 2 74513 Q8BNJ6 IP/WB
Straub C , et al. 2016
PICK1 protein interacting with PRKCA 1 84591 Q9EP80 Y2H; GST; IP/WB
Hirbec H , et al. 2003
PRKAA1 protein kinase, AMP-activated, alpha 1 catalytic subunit 65248 P54645 in vivo kinase assay; Phosphopeptide mapping
Raymond LA , et al. 1993
PRKCA protein kinase C, alpha 24680 Q9EP80 in vitro kinase assay; 2-D phosphopeptide mapping
Nasu-Nishimura Y , et al. 2009
SDCBP syndecan binding protein 53378 O08992 GST
Hirbec H , et al. 2002
SLC12A5 solute carrier family 12, member 5 57138 Q91V14 IP/WB; Co-localization
Mahadevan V , et al. 2014
UBC ubiquitin C 50522 Q63429 IP/WB
Salinas GD , et al. 2006

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