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GRIN2C (HGNC:4587) encodes the GluN2C subunit of the N-methyl-D-aspartate receptor (NMDAR), which mediates excitatory neurotransmission in the central nervous system. Alzheimer disease (MONDO:0004975) is characterized by progressive memory loss and cognitive decline, with a complex genetic architecture, especially in late-onset forms.
Exome sequencing in a large Italian pedigree with autosomal dominant late-onset Alzheimer disease revealed a rare missense variant, c.3215C>T (p.Ala1072Val), in GRIN2C that segregated with disease in 6 affected family members (PMID:39810256) and was absent in 9 unaffected relatives (PMID:39810256). No pathogenic variants were found in APP, PSEN1, PSEN2, or a panel of 77 neurodegeneration-associated genes.
The variant spectrum in GRIN2C for Alzheimer disease remains limited to this single founder mutation. Inheritance is autosomal dominant, with a total of 6 segregations reported across one pedigree. No additional recurrent or population-specific alleles have been described.
Functional assays in primary rat hippocampal neurons overexpressing GluN2C p.Ala1072Val demonstrated increased NMDAR-induced currents and an elevated surface/total receptor ratio, indicating enhanced receptor trafficking. Immunocytochemistry further revealed reduced colocalization of mutant GluN2C with 14-3-3 proteins, which normally facilitate NMDAR membrane delivery (PMID:39810256). These data support a gain-of-function mechanism leading to excitatory imbalance.
No conflicting reports have challenged the association of GRIN2C p.Ala1072Val with Alzheimer disease. While broader cohort studies are lacking, the combination of genetic segregation and concordant functional impact provides moderate clinical validity.
Overall, the identification of GRIN2C c.3215C>T (p.Ala1072Val) underscores a novel contribution of GluN2C-containing NMDARs to Alzheimer pathogenesis and suggests that genetic testing of GRIN2C may refine risk assessment and guide development of glutamatergic-targeted therapies.
Gene–Disease AssociationModerateVariant segregates in six affected family members across one pedigree with absence in nine unaffected relatives, supported by concordant functional assays Genetic EvidenceModerateSingle pedigree with six segregations of a rare missense variant in GRIN2C without other cases Functional EvidenceModerateIn vitro neuronal assays show increased NMDAR currents, elevated surface expression, and disrupted 14-3-3 colocalization |