Human Gene Module / Chromosome X / GRIA3

GRIA3glutamate ionotropic receptor AMPA type subunit 3

SFARI Gene Score
S
Syndromic Syndromic
Autism Reports / Total Reports
2 / 16
Rare Variants / Common Variants
41 / 1
Aliases
-
Associated Syndromes
-
Chromosome Band
Xq25
Associated Disorders
-
Relevance to Autism

Mutations in the GRIA3 gene are responsible for Wu-type X-linked syndromic intellectual developmental disorder (MRXSW; OMIM 300699); autistic behavior has been observed in a subset of individuals with GRIA3 variants (Wu et al., 2007; Chiyonobu et al., 2007; Guilmatre et al., 2009; Philips et al., 2014). Roy et al., 2021 found that GRIA3 exhibited high expression in the anterodorsal thalamus (AD) of mice, and that knockdown of this gene in AD thalamus resulted in memory deficits similar to those observed in AD thalamus-specific PTCHD1 knock-down mice.

Molecular Function

Glutamate receptors are the predominant excitatory neurotransmitter receptors in the mammalian brain and are activated in a variety of normal neurophysiologic processes. These receptors are heteromeric protein complexes composed of multiple subunits, arranged to form ligand-gated ion channels. The classification of glutamate receptors is based on their activation by different pharmacologic agonists. The subunit encoded by this gene belongs to a family of AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate)-sensitive glutamate receptors, and is subject to RNA editing (AGA->GGA; R->G). Alternative splicing at this locus results in different isoforms, which may vary in their signal transduction properties.

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
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SFARI Genomic Platforms
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Reports related to GRIA3 (16 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support - Chiyonobu T et al. (2007) No Autistic features
2 Primary - Wu Y et al. (2007) No Epilepsy/seizures, autistic behavior
3 Support - Bonnet C et al. (2009) No -
4 Support Recurrent rearrangements in synaptic and neurodevelopmental genes and shared biologic pathways in schizophrenia, autism, and mental retardation Guilmatre A , et al. (2009) Yes -
5 Support - Philips AK et al. (2014) No Autistic features
6 Support - Roy DS et al. (2021) No -
7 Support - Álvarez-Mora MI et al. (2022) No -
8 Support - Brea-Fernández AJ et al. (2022) No Epilepsy/seizures
9 Recent Recommendation - Singh T et al. (2022) No -
10 Support - Carvalho LML et al. (2022) No -
11 Support - Peng SX et al. (2022) No DD, ID, epilepsy/seizures, autistic features, ster
12 Support - Hu C et al. (2022) Yes -
13 Support - Chen Y et al. (2021) No -
14 Support - Okano S et al. (2023) No -
15 Support - Sanchis-Juan A et al. (2023) No -
16 Recent Recommendation - Berardo Rinaldi et al. (2024) No ASD, epilepsy/seizures, stereotypy
Rare Variants   (41)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss Familial Maternal - 17989220 Wu Y et al. (2007)
c.22G>A p.Gly8Arg missense_variant Unknown - - 35741772 Hu C et al. (2022)
- - copy_number_gain Familial Maternal - 17568425 Chiyonobu T et al. (2007)
c.1859G>C p.Gly620Ala missense_variant Unknown - - 35741772 Hu C et al. (2022)
- - copy_number_gain Familial Maternal Multiplex 19449417 Bonnet C et al. (2009)
- - copy_number_gain Familial Maternal Simplex 19736351 Guilmatre A , et al. (2009)
- p.Arg450Gln missense_variant Familial Maternal Simplex 17989220 Wu Y et al. (2007)
c.1888G>A p.Gly630Arg missense_variant Unknown - Unknown 35873028 Chen Y et al. (2021)
c.1982T>C p.Met661Thr missense_variant De novo - Simplex 36726007 Okano S et al. (2023)
c.1888G>C p.Gly630Arg missense_variant De novo - - 38038360 Berardo Rinaldi et al. (2024)
c.1960G>A p.Ala654Thr missense_variant De novo - - 38038360 Berardo Rinaldi et al. (2024)
c.1960G>C p.Ala654Pro missense_variant De novo - - 38038360 Berardo Rinaldi et al. (2024)
c.1961C>T p.Ala654Val missense_variant De novo - - 38038360 Berardo Rinaldi et al. (2024)
c.1979G>C p.Arg660Thr missense_variant De novo - - 38038360 Berardo Rinaldi et al. (2024)
c.1987T>C p.Ser663Pro missense_variant De novo - - 38038360 Berardo Rinaldi et al. (2024)
c.1994T>C p.Ile665Thr missense_variant Unknown - - 38038360 Berardo Rinaldi et al. (2024)
c.2101A>G p.Lys701Glu missense_variant De novo - - 38038360 Berardo Rinaldi et al. (2024)
c.2359G>A p.Glu787Lys missense_variant De novo - - 38038360 Berardo Rinaldi et al. (2024)
c.2396G>T p.Trp799Leu missense_variant De novo - - 38038360 Berardo Rinaldi et al. (2024)
c.2408G>A p.Gly803Glu missense_variant De novo - - 38038360 Berardo Rinaldi et al. (2024)
c.527C>A p.Ala176Glu missense_variant Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.1601T>A p.Ile534Lys missense_variant De novo - - 35322241 Brea-Fernández AJ et al. (2022)
- p.Arg631Ser missense_variant Familial Maternal Extended multiplex 17989220 Wu Y et al. (2007)
- p.Gly833Arg missense_variant Familial Maternal Extended multiplex 17989220 Wu Y et al. (2007)
- p.Met706Thr missense_variant Familial Maternal Extended multiplex 17989220 Wu Y et al. (2007)
c.1888G>C p.Gly630Arg missense_variant Familial Maternal Simplex 35697757 Peng SX et al. (2022)
c.2360A>G p.Glu787Gly missense_variant Familial Maternal Simplex 35697757 Peng SX et al. (2022)
c.1474G>A p.Gly492Ser missense_variant Familial Maternal - 38038360 Berardo Rinaldi et al. (2024)
c.1888G>C p.Gly630Arg missense_variant Familial Maternal - 38038360 Berardo Rinaldi et al. (2024)
c.1964T>C p.Phe655Ser missense_variant Familial Maternal - 38038360 Berardo Rinaldi et al. (2024)
c.2359G>A p.Glu787Lys missense_variant Familial Maternal - 38038360 Berardo Rinaldi et al. (2024)
c.2360A>G p.Glu787Gly missense_variant Familial Maternal - 38038360 Berardo Rinaldi et al. (2024)
c.2408G>C p.Gly803Ala missense_variant Familial Maternal - 38038360 Berardo Rinaldi et al. (2024)
c.1888G>C p.Gly630Arg missense_variant Familial Maternal Multiplex 35697757 Peng SX et al. (2022)
c.2440-2734C>T - missense_variant Familial Maternal Multiplex 37541188 Sanchis-Juan A et al. (2023)
c.2638T>A p.Tyr880Asn missense_variant Familial Maternal - 35322241 Brea-Fernández AJ et al. (2022)
c.2038_2040delinsTGT p.Gly680Cys missense_variant De novo - Simplex 35597848 Carvalho LML et al. (2022)
c.1957G>A p.Ala653Thr missense_variant Familial Maternal Multiplex 38038360 Berardo Rinaldi et al. (2024)
c.1892G>A p.Arg631His missense_variant Familial Maternal Simplex 35183220 Álvarez-Mora MI et al. (2022)
c.1888G>C p.Gly630Arg missense_variant Familial Maternal Extended multiplex 24721225 Philips AK et al. (2014)
c.1112_1116del p.Gln371ArgfsTer6 frameshift_variant Familial Maternal - 38038360 Berardo Rinaldi et al. (2024)
Common Variants   (1)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
- - intron_variant - - - 35697757 Peng SX et al. (2022)
SFARI Gene score
S

Syndromic

Score Delta: Score remained at S

criteria met
See SFARI Gene'scoring criteria
S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

Krishnan Probability Score

Score 0.64050441237497

Ranking 52/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.99865377764627

Ranking 1144/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.94304823175193

Ranking 15538/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Zhang D Score

Score 0.26629239651474

Ranking 3239/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
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