GRM1 – Autosomal Recessive Spinocerebellar Ataxia 13

GRM1 encodes the metabotropic glutamate receptor 1 (mGluR1), a G protein-coupled receptor critical for cerebellar Purkinje cell function. Pathogenic biallelic GRM1 variants underlie autosomal recessive spinocerebellar ataxia 13 (SCAR13) through loss-of-function mechanisms.

Affected individuals present with early-onset global developmental delay, stance and gait ataxia, dysarthria, dysdiadochokinesia, dysmetria and cerebellar atrophy on MRI. Ten patients from a Roma founder population were homozygous for GRM1 variants, including c.2651G>A (p.Gly884Glu) ([PMID:22901947]).

Segregation analysis in five unrelated consanguineous families confirmed full cosegregation of recessive alleles with disease status ([PMID:22901947]). All affected relatives were homozygous and unaffected carriers were heterozygous, supporting autosomal recessive inheritance.

Molecular studies in patient-derived lymphoblastoid cells demonstrated that exon 8 deletion and intron 8 splice variants (c.2652_2654del and c.2660+2T>G) result in aberrant transcripts lacking transmembrane domains and complete loss of functional mGluR1 protein ([PMID:22901947]).

Animal models recapitulate the human phenotype: the crv4 BALB/c mouse with an intronic LTR insertion in Grm1 shows ataxic gait and absent mGluR1 ([PMID:16964410]); rcw/nmf373 allelic series in mice bearing Grm1 missense and duplication mutations display early-onset ataxia without neurodegeneration ([PMID:17934773]).

Collectively, genetic and functional data meet ClinGen criteria for a Strong gene–disease association. Loss of mGluR1 function causes SCAR13 and models show rescue potential via receptor restoration. Key Take-home: Biallelic GRM1 loss-of-function variants cause autosomal recessive spinocerebellar ataxia 13 with consistent clinical and model-based evidence.

References

• American Journal of Human Genetics • 2012 • Autosomal-recessive congenital cerebellar ataxia is caused by mutations in metabotropic glutamate receptor 1 PMID:22901947
• International Journal of Molecular Medicine • 2006 • crv4, a mouse model for human ataxia associated with kyphoscoliosis caused by an mRNA splicing mutation of the metabotropic glutamate receptor 1 (Grm1). PMID:16964410
• Mammalian Genome • 2007 • The mouse mutants recoil wobbler and nmf373 represent a series of Grm1 mutations. PMID:17934773

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