GRIN2A – Epilepsy

GRIN2A encodes the GluN2A subunit of N-methyl-D-aspartate receptors (NMDARs), ligand-gated ion channels critical for excitatory neurotransmission. Pathogenic variants in GRIN2A have been repeatedly identified in patients with epilepsy, particularly early-onset epileptic encephalopathies and epilepsy-aphasia spectrum disorders. Epilepsy phenotypes range from benign focal seizures to refractory epileptic encephalopathy, often accompanied by developmental delay and cerebral atrophy ([PMID:24504326]).

Inheritance is predominantly autosomal dominant with a high rate of de novo missense mutations and occasional inherited splice or nonsense variants. Across studies, 248 unrelated individuals with epilepsy harbored GRIN2A variants, including missense, nonsense, splice-site, and frameshift alleles, with at least one recurrent variant c.2434C>A (p.Leu812Met) mentioned in multiple reports ([PMID:30544257]).

Segregation of GRIN2A variants has been observed in multi-generation pedigrees and familial mosaicism. Six affected relatives in three independent families showed co-segregation of GRIN2A splice-site or missense variants with epilepsy and speech impairments, underscoring dominant inheritance ([PMID:20890276]; [PMID:39084904]).

Functional studies consistently demonstrate a gain-of-function mechanism: the Leu812Met and Met817Val substitutions enhance glutamate potency, reduce sensitivity to Mg²⁺, protons, and zinc, prolong synaptic-like current decay, and increase channel open probability, driving neuronal hyperexcitability ([PMID:24504326]; [PMID:28126851]).

Rescue pharmacology with NMDAR channel blockers shows that GRIN2A-L812M and related variants retain memantine sensitivity, with adjunct memantine therapy reducing seizure burden in a proband, illustrating a precision medicine approach ([PMID:24839611]).

References

• Nature communications • 2014 • Functional analysis of a de novo GRIN2A missense mutation associated with early-onset epileptic encephalopathy PMID:24504326
• Nature genetics • 2010 • Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes PMID:20890276
• Molecular pharmacology • 2017 • Functional Evaluation of a De Novo GRIN2A Mutation Identified in a Patient with Profound Global Developmental Delay and Refractory Epilepsy PMID:28126851
• Brain • 2019 • GRIN2A-related disorders: genotype and functional consequence predict phenotype PMID:30544257
• Annals of clinical and translational neurology • 2014 • GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine PMID:24839611
• European journal of paediatric neurology • 2017 • Epilepsy in patients with GRIN2A alterations: Genetics, neurodevelopment, epileptic phenotype and response to anticonvulsive drugs PMID:28109652

Evidence Based Scoring (AI generated)