GRIK2 – autosomal recessive non-syndromic intellectual disability

GRIK2 encodes the GluK2 subunit of kainate-type ionotropic glutamate receptors, which are critical mediators of excitatory neurotransmission and synaptic plasticity. Early genetic surveys of consanguineous families reported GRIK2 among four genes implicated in autosomal recessive non-syndromic intellectual disability (NS-AR ID) alongside PRSS12, CRBN, and CC2D1A, but no specific pathogenic variants have been described to date (PMID:18452889).

Inheritance of GRIK2-related NS-AR ID is presumed autosomal recessive based on the familial clustering of affected sibships in initial linkage studies. However, no homozygous or compound heterozygous coding mutations in GRIK2 have been reported in affected individuals, and segregation data are lacking.

Functional assays of GluK2 receptor biogenesis and topology demonstrate that N-linked glycosylation at asparagine residues 515 and 720 is required for proper extracellular folding and ER exit, and site-directed mutagenesis at these sites alters receptor currents (PMID:8188697). Electrophysiological and trafficking studies in heterologous systems confirm that glycosylation-deficient GluK2 receptors exhibit reduced kainate-mediated currents, underscoring the importance of GluK2 in neuronal signaling, although these studies were not performed in cells from NS-AR ID patients.

A linkage and association study in idiopathic generalized epilepsies excluded GRIK2 as a major IGE susceptibility locus, highlighting disease-specific effects of GRIK2 variants (PMID:7675232). No conflicting reports directly dispute the involvement of GRIK2 in NS-AR ID, but the absence of disease-segregating variants tempers confidence in the gene-disease link.

Taken together, GRIK2 remains a plausible NS-AR ID gene given its central role in excitatory synaptic transmission and early genetic nominations, but evidence is limited by lack of identified pathogenic alleles and family segregation. Future studies identifying homozygous or compound heterozygous GRIK2 mutations with cosegregation and patient-derived functional assays will be essential to establish clinical validity. Key take-home: although GRIK2 is an attractive candidate for autosomal recessive non-syndromic intellectual disability, current data are insufficient for clinical diagnostic use.

References

• American Journal of Human Genetics • 2008 • A defect in the TUSC3 gene is associated with autosomal recessive mental retardation. PMID:18452889
• The Journal of Biological Chemistry • 1994 • A transmembrane model for an ionotropic glutamate receptor predicted on the basis of the location of asparagine-linked oligosaccharides. PMID:8188697
• Neurology • 1995 • Refinement of map position of the human GluR6 kainate receptor gene (GRIK2) and lack of association and linkage with idiopathic generalized epilepsies. PMID:7675232

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