Spinocerebellar Ataxia 44 Caused by a Novel GRM1 Variant: Reviewing the Contrasting Pathogenic Mechanisms Underlying Two GRM1-Associated Hereditary Ataxias.

GRM1 encodes type 1 metabotropic glutamate receptor (mGluR1). Its pathogenic variants are associated with the rare autosomal recessive cerebellar ataxia 13 (SCAR13) due to loss of mGluR1 function, and the even rarer spinocerebellar ataxia 44 (SCA44) due to a gain-of-function molecular basis. We report a new case of SCA44 caused by a novel and de novo GRM1 variant c.2303 C > T (p.Thr768Ile), which was considered "likely pathogenic" by the American College of Medical Genetic criteria (PS2, PM2, PP3). This variant was predicted to lead to a stability effect on mGluR1 in the evaluation with DynaMut2, like the other known SCA44 GRM1 variants and in contrast to lower stability or destabilizing effects for SCAR13 missense variants. The affected residue Thr768 was located close to the binding pockets of allosteric modulators and within the highly conserved cholesterol recognition association/interaction consensus motif. Collectively, this novel GRM1 variant caused SCA44 by increasing the constitutive activity of mGluR1. Our findings underscore the distinct molecular mechanisms of mGluR1 aberration for the two GRM1-associated hereditary ataxias, and provide a mechanism-relevant prospect in the pharmacological therapies for restoring mGluR1 function.