GRIN1

Chr 9ARAD

glutamate ionotropic receptor NMDA type subunit 1

ENSG00000176884 UniProt: Q05586 OMIM: 138249

The protein is the GluN1 subunit of NMDA receptors, which form heterotetrameric ligand-gated calcium channels essential for synaptic plasticity, learning, and memory formation. Mutations cause developmental and epileptic encephalopathy and neurodevelopmental disorders with or without hyperkinetic movements and seizures through both autosomal dominant and autosomal recessive inheritance patterns. The gene is highly constrained against loss-of-function variants, and mutations can cause disease through multiple mechanisms depending on the specific variant type and location.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Component of N-methyl-D-aspartate (NMDA) receptors (NMDARs) that function as heterotetrameric, ligand-gated cation channels with high calcium permeability and voltage-dependent block by Mg(2+) (PubMed:21376300, PubMed:26875626, PubMed:26919761, PubMed:28126851, PubMed:28228639, PubMed:36959261, PubMed:7679115, PubMed:7681588, PubMed:7685113). NMDARs participate in synaptic plasticity for learning and memory formation by contributing to the long-term potentiation (LTP) (PubMed:26875626). Channel activation requires binding of the neurotransmitter L-glutamate to the GluN2 subunit, glycine or D-serine binding to the GluN1 subunit, plus membrane depolarization to eliminate channel inhibition by Mg(2+) (PubMed:21376300, PubMed:26875626, PubMed:26919761, PubMed:27164704, PubMed:28095420, PubMed:28105280, PubMed:28126851, PubMed:28228639, PubMed:36959261, PubMed:38538865, PubMed:7679115, PubMed:7681588, PubMed:7685113). NMDARs mediate simultaneously the potassium efflux and the influx of calcium and sodium (By similarity). Each GluN2 or GluN3 subunit confers differential attributes to channel properties, including activation, deactivation and desensitization kinetics, pH sensitivity, Ca2(+) permeability, and binding to allosteric modulators (PubMed:26875626, PubMed:26919761, PubMed:36309015, PubMed:38598639)

OMIM ResearchGenerating clinical summary…

LOFmechanismAR/ADLOEUF 0.313 OMIM phenotypes

VCEP Guidelines: GRIN DisordersPilot

ClinGen Panel

Clinical Summary— GRIN1

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Gene-Disease Validity (ClinGen)

complex neurodevelopmental disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.98). One damaged copy is likely sufficient to cause disease.

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.31LOEUF

pLI 0.976

Z-score 5.25

OE 0.17 (0.10–0.31)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

6.22Z-score

OE missense 0.28 (0.24–0.32)

163 obs / 586.7 exp

Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios?

LoF OE?0.17 (0.10–0.31)

0≤0.351.4

Missense OE?0.28 (0.24–0.32)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 8 / 46.8Missense obs/exp: 163 / 586.7Syn Z: 0.67

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveGRIN1-related epileptic encephalopathyOTHERAD

definitiveGRIN1-related neurodevelopmental disorder with or without hyperkinetic movements and seizuresLOFAR

This gene — mechanism propensity

0.5378th %ile

GOF

0.6639th %ile

LOF

0.58top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, gain-of-function and dominant-negative). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFLOEUF 0.31

GOFprediction above median

DN1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNMutations cluster within transmembrane segments and result in loss of channel function of varying severity with a dominant-negative effect.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References