GRM1 – Spinocerebellar Ataxia 44

GRM1 encodes the metabotropic glutamate receptor 1 (mGluR1), a G_q/11-coupled receptor highly expressed in cerebellar Purkinje cells. Gain-of-function heterozygous variants in GRM1 underlie autosomal dominant Spinocerebellar Ataxia 44, characterized by progressive gait ataxia and dyscoordination. A single de novo missense variant, c.2303C>T (p.Thr768Ile), was identified in a patient presenting with onset in mid adulthood, absent from gnomAD, and predicted by DynaMut2 to increase receptor stability near allosteric binding pockets (PMID:40199824).

Pharmacological profiling in Flp-In T Rex HEK293A cells of SCA44-associated mGluR1 mutants (including Y792C) revealed enhanced constitutive activity, reduced orthosteric agonist potency, and altered cooperativity, whereas negative allosteric modulators restored glutamate responsiveness in both Ca^2+ mobilization and IP_1 accumulation assays (PMID:39030902). These data define a gain-of-function mechanism amenable to allosteric modulation. Although clinical evidence is limited to one proband, concordant in silico and in vitro findings support a Limited genetic association with Moderate functional evidence for GRM1 in SCA44. GRM1 should be included in diagnostic ataxia panels, and allosteric modulators may represent targeted therapeutic options.

References

• Cerebellum (London, England) • 2025 • Spinocerebellar Ataxia 44 Caused by a Novel GRM1 Variant: Reviewing the Contrasting Pathogenic Mechanisms Underlying Two GRM1-Associated Hereditary Ataxias PMID:40199824
• British Journal of Pharmacology • 2024 • SCA44- and SCAR13-associated GRM1 mutations affect metabotropic glutamate receptor 1 function through distinct mechanisms PMID:39030902

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