Human Gene Module / Chromosome X / GLRA2

GLRA2glycine receptor, alpha 2

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
7 / 17
Rare Variants / Common Variants
17 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
Xp22.2
Associated Disorders
SCZ
Relevance to Autism

A maternally-inherited missense variant in the GLRA2 gene was identified in a female ASD proband in Piton et al., 2011; subsequent functional analysis of this variant in Zhang et al., 2017 demonstrated properties consistent with an overall gain-of-function effect, such as reduced glycine sensitivity and significantly increased inhibitory postsynaptic current (IPSC) rise and decay times. De novo missense variants in this gene have also been identified in individuals with ASD (Iossifov et al., 2012; Iossifov et al., 2014; Pilorge et al., 2016). Pilorge et al., 2016 demonstrated that two of these missense variants resulted in impaired surface expression and reduced sensitivity to glycine; in the same report, a maternally-inherited 151 kb microdeletion affecting the GLRA2 gene that was identified in a male patient with non-syndromic autism was shown to impair cell membrane localization and resulted in failure to rescue axon-branching defects in spinal motor axons in zebrafish with targeted glra2 knockdown. Functional analysis of the ASD-associated p.Asn136Ser missense variant, which was originally identified in an SSC proband, in Drosophila in Marcogliese et al., 2022 demonstrated a loss-of-function effect (mutant flies were capable of copulating within trial period similar to TG4 mutant alone, compared to a failure to copulate observed in humanized reference flies; failure to reduce expected viability to the extent of corresponding reference allele upon ubiquitous overexpression; electroretinogram recordings on fly eyes expressing human GLRA2 demonstrated that expression of mutant GLRA2 in pre-synaptic photoreceptors resulted in a decrease in amplitude of "OFF" transients, indicating a decrease in synaptic tranmission). Marcogliese et al., 2022 also characterized 13 unrelated individuals with GLRA2 missense variants (8 females with de novo variants and 5 males with maternally-inherited variants); all 13 individuals presented with developmental delay/intellectual disability, and autism spectrum disorder was reported in four (one female, three males).

Molecular Function

A ligand-gated channel mediating a chloride-dependent inhibitory neurotransmission

External Links
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Human
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Mouse
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SFARI Genomic Platforms
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Reports related to GLRA2 (17 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited Alternative splicing generates two variants of the alpha 1 subunit of the inhibitory glycine receptor Malosio ML , et al. (1991) No -
2 Recent Recommendation Glycinergic transmission in the Mammalian retina Wssle H , et al. (2009) No -
3 Recent Recommendation Differential expression of glycine receptor subunits in the rat basolateral and central amygdala Delaney AJ , et al. (2009) No -
4 Recent Recommendation Ginkgolide X is a potent antagonist of anionic Cys-loop receptors with a unique selectivity profile at glycine receptors Jensen AA , et al. (2010) No -
5 Primary Systematic resequencing of X-chromosome synaptic genes in autism spectrum disorder and schizophrenia Piton A , et al. (2010) Yes SCZ
6 Support Whole-exome sequencing and homozygosity analysis implicate depolarization-regulated neuronal genes in autism Chahrour MH , et al. (2012) Yes -
7 Support De novo gene disruptions in children on the autistic spectrum Iossifov I , et al. (2012) Yes -
8 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
9 Support Large-scale discovery of novel genetic causes of developmental disorders Deciphering Developmental Disorders Study (2014) No -
10 Recent Recommendation Genetic and functional analyses demonstrate a role for abnormal glycinergic signaling in autism Pilorge M , et al. (2015) Yes -
11 Support Structure-Function Analysis of the GlyR ?2 Subunit Autism Mutation p.R323L Reveals a Gain-of-Function Zhang Y , et al. (2017) No -
12 Support ?2-glycine receptors modulate adult hippocampal neurogenesis and spatial memory Lin MS , et al. (2017) No -
13 Support Alpha2-Containing Glycine Receptors Promote Neonatal Spontaneous Activity of Striatal Medium Spiny Neurons and Support Maturation of Glutamatergic Inputs Comhair J , et al. (2018) No -
14 Support Autism-associated missense genetic variants impact locomotion and neurodevelopment in Caenorhabditis elegans Wong WR , et al. (2019) Yes -
15 Recent Recommendation - Marcogliese PC et al. (2022) Yes DD, ID, epilepsy/seizures
16 Support - Chen X et al. (2022) No ASD
17 Highly Cited Dendritic and postsynaptic localizations of glycine receptor alpha subunit mRNAs Racca C , et al. (1997) No -
Rare Variants   (17)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss Familial Maternal Simplex 26370147 Pilorge M , et al. (2015)
c.140T>C p.Phe47Ser missense_variant De novo - - 35294868 Marcogliese PC et al. (2022)
c.887C>T p.Thr296Met missense_variant De novo - - 35294868 Marcogliese PC et al. (2022)
c.718A>G p.Lys240Glu missense_variant Familial Maternal - 35571374 Chen X et al. (2022)
c.16G>C p.Val6Leu missense_variant De novo - Simplex 22542183 Iossifov I , et al. (2012)
c.407A>G p.Asn136Ser missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.1049G>T p.Arg350Leu missense_variant Familial Maternal - 20479760 Piton A , et al. (2010)
c.458G>A p.Arg153Gln missense_variant De novo - Multiplex 26370147 Pilorge M , et al. (2015)
c.777C>G p.Ile259Met missense_variant De novo - Simplex 35294868 Marcogliese PC et al. (2022)
c.887C>T p.Thr296Met missense_variant De novo - Simplex 35294868 Marcogliese PC et al. (2022)
c.754C>T p.Arg252Cys missense_variant Familial Maternal - 35294868 Marcogliese PC et al. (2022)
c.1199C>T p.Pro400Leu missense_variant Familial Maternal - 35294868 Marcogliese PC et al. (2022)
c.1261A>G p.Ile421Val missense_variant Familial Maternal Multiplex 22511880 Chahrour MH , et al. (2012)
c.1186C>A p.Pro396Thr missense_variant Familial Maternal Simplex 35294868 Marcogliese PC et al. (2022)
c.1334G>A p.Arg445Gln missense_variant Familial Maternal Simplex 35294868 Marcogliese PC et al. (2022)
c.862G>A p.Ala288Thr missense_variant Familial Maternal Multiplex 35294868 Marcogliese PC et al. (2022)
c.887C>T p.Thr296Met missense_variant De novo - Unknown 25533962 Deciphering Developmental Disorders Study (2014)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

A maternally-inherited missense variant in the GLRA2 gene was identified in a female ASD proband in Piton et al., 2011; subsequent functional analysis of this variant in Zhang et al., 2017 demonstrated properties consistent with an overall gain-of-function effect, such as reduced glycine sensitivity and significantly increased inhibitory postsynaptic current (IPSC) rise and decay times. De novo missense variants in this gene have also been identified in individuals with ASD (Iossifov et al., 2012; Iossifov et al., 2014; Pilorge et al., 2016). Pilorge et al., 2016 demonstrated that two of these missense variants resulted in impaired surface expression and reduced sensitivity to glycine; in the same report, a maternally-inherited 151 kb microdeletion affecting the GLRA2 gene that was identified in a male patient with non-syndromic autism was shown to impair cell membrane localization and resulted in failure to rescue axon-branching defects in spinal motor axons in zebrafish with targeted glra2 knockdown.

Score Delta: Score remained at 2

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

4/1/2022
3
icon
2

Decreased from 3 to 2

Description

A maternally-inherited missense variant in the GLRA2 gene was identified in a female ASD proband in Piton et al., 2011; subsequent functional analysis of this variant in Zhang et al., 2017 demonstrated properties consistent with an overall gain-of-function effect, such as reduced glycine sensitivity and significantly increased inhibitory postsynaptic current (IPSC) rise and decay times. De novo missense variants in this gene have also been identified in individuals with ASD (Iossifov et al., 2012; Iossifov et al., 2014; Pilorge et al., 2016). Pilorge et al., 2016 demonstrated that two of these missense variants resulted in impaired surface expression and reduced sensitivity to glycine; in the same report, a maternally-inherited 151 kb microdeletion affecting the GLRA2 gene that was identified in a male patient with non-syndromic autism was shown to impair cell membrane localization and resulted in failure to rescue axon-branching defects in spinal motor axons in zebrafish with targeted glra2 knockdown.

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

A maternally-inherited missense variant in the GLRA2 gene was identified in a female ASD proband in Piton et al., 2011; subsequent functional analysis of this variant in Zhang et al., 2017 demonstrated properties consistent with an overall gain-of-function effect, such as reduced glycine sensitivity and significantly increased inhibitory postsynaptic current (IPSC) rise and decay times. De novo missense variants in this gene have also been identified in individuals with ASD (Iossifov et al., 2012; Iossifov et al., 2014; Pilorge et al., 2016). Pilorge et al., 2016 demonstrated that two of these missense variants resulted in impaired surface expression and reduced sensitivity to glycine; in the same report, a maternally-inherited 151 kb microdeletion affecting the GLRA2 gene that was identified in a male patient with non-syndromic autism was shown to impair cell membrane localization and resulted in failure to rescue axon-branching defects in spinal motor axons in zebrafish with targeted glra2 knockdown.

Reports Added
[New Scoring Scheme]
7/1/2019
4
icon
4

Decreased from 4 to 4

Description

A maternally-inherited missense variant in the GLRA2 gene was identified in a female ASD proband in Piton et al., 2011; subsequent functional analysis of this variant in Zhang et al., 2017 demonstrated properties consistent with an overall gain-of-function effect, such as reduced glycine sensitivity and significantly increased inhibitory postsynaptic current (IPSC) rise and decay times. De novo missense variants in this gene have also been identified in individuals with ASD (Iossifov et al., 2012; Iossifov et al., 2014; Pilorge et al., 2016). Pilorge et al., 2016 demonstrated that two of these missense variants resulted in impaired surface expression and reduced sensitivity to glycine; in the same report, a maternally-inherited 151 kb microdeletion affecting the GLRA2 gene that was identified in a male patient with non-syndromic autism was shown to impair cell membrane localization and resulted in failure to rescue axon-branching defects in spinal motor axons in zebrafish with targeted glra2 knockdown.

Reports Added
[Autism-associated missense genetic variants impact locomotion and neurodevelopment in Caenorhabditis elegans.2019]
10/1/2018
5
icon
4

Decreased from 5 to 4

Description

A maternally-inherited missense variant in the GLRA2 gene was identified in a female ASD proband in Piton et al., 2011; subsequent functional analysis of this variant in Zhang et al., 2017 demonstrated properties consistent with an overall gain-of-function effect, such as reduced glycine sensitivity and significantly increased inhibitory postsynaptic current (IPSC) rise and decay times. De novo missense variants in this gene have also been identified in individuals with ASD (Iossifov et al., 2012; Iossifov et al., 2014; Pilorge et al., 2016). Pilorge et al., 2016 demonstrated that two of these missense variants resulted in impaired surface expression and reduced sensitivity to glycine; in the same report, a maternally-inherited 151 kb microdeletion affecting the GLRA2 gene that was identified in a male patient with non-syndromic autism was shown to impair cell membrane localization and resulted in failure to rescue axon-branching defects in spinal motor axons in zebrafish with targeted glra2 knockdown.

Reports Added
[Alpha2-Containing Glycine Receptors Promote Neonatal Spontaneous Activity of Striatal Medium Spiny Neurons and Support Maturation of Glutamatergic ...2018]
10/1/2017
5
icon
5

Decreased from 5 to 5

Description

Rare mutations in the GLRA2 gene have been identified with autism (Piton et al., 2011).

Reports Added
[2-glycine receptors modulate adult hippocampal neurogenesis and spatial memory.2017]
7/1/2017
5
icon
5

Decreased from 5 to 5

Description

Rare mutations in the GLRA2 gene have been identified with autism (Piton et al., 2011).

Reports Added
[Structure-Function Analysis of the GlyR 2 Subunit Autism Mutation p.R323L Reveals a Gain-of-Function.2017]
1/1/2016
5
icon
5

Decreased from 5 to 5

Description

Rare mutations in the GLRA2 gene have been identified with autism (Piton et al., 2011).

Reports Added
[Systematic resequencing of X-chromosome synaptic genes in autism spectrum disorder and schizophrenia.2010] [Whole-exome sequencing and homozygosity analysis implicate depolarization-regulated neuronal genes in autism.2012] [De novo gene disruptions in children on the autistic spectrum.2012] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Alternative splicing generates two variants of the alpha 1 subunit of the inhibitory glycine receptor.1991] [Dendritic and postsynaptic localizations of glycine receptor alpha subunit mRNAs.1997] [Glycinergic transmission in the Mammalian retina.2009] [Differential expression of glycine receptor subunits in the rat basolateral and central amygdala.2009] [Ginkgolide X is a potent antagonist of anionic Cys-loop receptors with a unique selectivity profile at glycine receptors.2010] [Genetic and functional analyses demonstrate a role for abnormal glycinergic signaling in autism.2015] [The contribution of de novo coding mutations to autism spectrum disorder2014]
1/1/2015
5
icon
5

Decreased from 5 to 5

Description

Rare mutations in the GLRA2 gene have been identified with autism (Piton et al., 2011).

Reports Added
[Large-scale discovery of novel genetic causes of developmental disorders.2014]
7/1/2014
No data
icon
5

Increased from No data to 5

Description

Rare mutations in the GLRA2 gene have been identified with autism (Piton et al., 2011).

4/1/2014
No data
icon
5

Increased from No data to 5

Description

Rare mutations in the GLRA2 gene have been identified with autism (Piton et al., 2011).

Krishnan Probability Score

Score 0.5019027997471

Ranking 1994/25841 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 0.90858763229945

Ranking 3157/18225 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 0.72931669676599

Ranking 1368/18665 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
Larsen Cumulative Evidence Score

Score 5

Ranking 280/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Original Source
Zhang D Score

Score 0.060924754799852

Ranking 6962/20870 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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