GRIA4

protein-coding

glutamate ionotropic receptor AMPA type subunit 4, the group of Glutamate ionotropic receptor AMPA type subunits

Gene summary

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 of this gene results in transcript variants encoding different isoforms, which may vary in their signal transduction properties. Some haplotypes of this gene show a positive association with schizophrenia. [provided by RefSeq, Jul 2008]

Previous symbols:

GLUR4

MANE transcript

NM_000829.4

Inheritance

ClinVar variants

P:11U:228B:52

Top phenotype

Neurodevelopmental disorder with or without seizures and gait abnormalities

gnomAD constraint

pLI —, LoF o/e 0.27

Max pathogenic AF

—

Genomic locus

chr11:105,609,535-105,982,090

External References & Databases

Ensembl (ENSG00000152578)

Transcript & Mutation Effects

hg38 • Region Span ~372.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorder with or without seizures and gait abnormalitiesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0060641

Submitter: Labcorp Genetics (formerly Invitae)

neurodevelopmental disorder with or without seizures and gait abnormalitiesMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0060641

Submitter: Illumina

neurodevelopmental disorder with or without seizures and gait abnormalitiesLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0060641

Submitter: G2P

neurodevelopmental disorder with or without seizures and gait abnormalitiesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0060641

Submitter: PanelApp Australia

neurodevelopmental disorder with or without seizures and gait abnormalitiesMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0060641

Submitter: Ambry Genetics

neurodevelopmental disorder with or without seizures and gait abnormalitiesMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0060641

Submitter: ClinGen

*GRIA4* was first reported in detail in relation to autosomal dominant neurodevelopmental disorder with or without seizures and gait abnormalities in 2017 (Martin et al., PMID: 29220673); variants in *GRIA4* had been documented previously but without detailed phenotypic information (Lelieveld et al., 2016, PMID: 27479843). The condition is characterized by developmental delay, intellectual disability, tone abnormalities (mostly in the form of hypertonia or spasticity), abnormal gait, as well as seizures and/or EEG abnormalities in some individuals. Ten unique missense variants reported in 10 probands in 5 publications (PMIDs: 27479843, 29220673, 35518358, 37921875, 38819422) are included in this curation (for a total of 7 points). This gene-disease relationship is also supported by experimental evidence, including biochemical evidence and a mouse model. Specifically, AMPA-type ionotropic glutamate receptors are homomeric or heteromeric assemblies of four core subunits (GluA1-4). Variants in *GRIA1*, *GRIA2* and *GRIA3*, encoding the GluA1, GluA2 and GluA3 subunits, respectively, are known to cause developmental disorders with developmental delay, intellectual disability, autistic features and seizures among the reported phenotypes (PMID: 27080385). In a mouse model, genetic deficiency of *Gria4* either in the form of reduction or complete lack of *Gria4* was associated with high frequency spike wave discharges and behavioral arrest, modeling absence epilepsy. The model appeared to be more consistent with recessive inheritance with spike wave discharges, also observed with lower incidence in the context of heterozygosity (PMID: 18316356). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has been reported. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on July 7, 2024 (SOP Version 10).

Clinical Genomic Database (CGD)

Neurodevelopmental disorder with or without seizures and gait abnormalitiesAD

Manifestation: Craniofacial; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 29220673

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GRIA4 variants in ClinVar

10 Conditions Cataloged

not providedTotal: 160

Inborn genetic diseasesTotal: 79

Neurodevelopmental disorder with or without seizures and gait abnormalitiesTotal: 55

not specifiedTotal: 52

GRIA4-related disorderTotal: 27

Intellectual disabilityTotal: 6

See casesTotal: 3

GRIA4-related neurodevelopmental disorderTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000829.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous				39 clinvar	1 clinvar	40
missense	2 clinvar	7 clinvar	211 clinvar	12 clinvar		232
nonsense		2 clinvar	3 clinvar			5
start loss			1 clinvar			1
frameshift			7 clinvar			7
splice donor/acceptor (+/-2bp)			6 clinvar			6
Total	2	9	228	51	1	291

Highest pathogenic variant AF is 0.000032954787

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 50 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000829.4	RefSeq	NP_000820.4	16	MANE Select
ENST00000282499.10	Ensembl	ENSP00000282499.5	16	MANE Select
NM_001077243.3	RefSeq	NP_001070711.3	15	Standard
NM_001077244.2	RefSeq	NP_001070712.1	10	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Retrograde endocannabinoid signaling - Homo sapiens (human)
Dopaminergic synapse - Homo sapiens (human)
Glutamatergic synapse - Homo sapiens (human)
Nicotine addiction - Homo sapiens (human)
Circadian entrainment - Homo sapiens (human)

Biological Process

glutamate receptor signaling pathway
ion transmembrane transport
ionotropic glutamate receptor signaling pathway

Molecular Function

amyloid-beta binding
ionotropic glutamate receptor activity
AMPA glutamate receptor activity

Cellular Component

plasma membrane
cell junction
endocytic vesicle membrane
AMPA glutamate receptor complex
neuronal cell body

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000282499
Coding exons: 16
Length: 372099
Individuals with no LoFs: 125728
Homozygous LoFs: 0
Heterozygous LoFs: 20
Defined: 125748
p: 0.0000795

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.42	278	491	0.566	0.0000246	5907
Missense (PolyPhen)		75	213.31	0.35161		2612
Synonymous	-0.472	185	177	1.05	0.00000969	1731
Loss of Function	4.70	13	48.2	0.270	0.00000280	554

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0.000093	0.000092	rare
European (Non-Finnish)	0.00011	0.00011	rare
South Asian	0.000069	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Receptor for glutamate that functions as ligand-gated ion channel in the central nervous system and plays an important role in excitatory synaptic transmission. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. Binding of the excitatory neurotransmitter L- glutamate induces a conformation change, leading to the opening of the cation channel, and thereby converts the chemical signal to an electrical impulse. The receptor then desensitizes rapidly and enters a transient inactive state, characterized by the presence of bound agonist. In the presence of CACNG4 or CACNG7 or CACNG8, shows resensitization which is characterized by a delayed accumulation of current flux upon continued application of glutamate. {ECO:0000269|PubMed:21172611}.;
Disease: DISEASE: Neurodevelopmental disorder with or without seizures and gait abnormalities (NEDSGA) [MIM:617864]: An autosomal dominant neurodevelopmental disorder characterized by global developmental delay apparent from infancy or early childhood, mild to profound intellectual disability, hypertonia early in life, which progresses to spasticity and impaired gait later, and behavioral abnormalities. Some patients may develop seizures of variable severity early in life. {ECO:0000269|PubMed:29220673}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.189

Intolerance Scores

LoFtool: 0.0934
RVIS EVS: -1.09
RVIS percentile EVS: 7.05

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.815

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium