Identification of a novel glutamate receptor 2 mutation in mice presenting progressive cerebellar ataxia.

Ataxia is a condition characterized by impaired coordination of movements due to dysfunction of the cerebellum or related neural circuits. Here, we describe a mouse colony exhibiting progressive ataxia that arose spontaneously, which we have designated td. Whole genome sequencing and gene mapping revealed a 0.2 Mb tandem duplication involving exons 3 and 4 of the Grid2 gene, leading to premature termination of translation and reduced mRNA expression. Consistent with previous reports, our findings indicate that both structural and transcriptional abnormalities of Grid2 contribute to the observed phenotype. Notably, this type of variant in the Grid2 gene has not been identified. We observed atrophy of the granular and molecular layers and neuroinflammation in the granular layer of the td cerebellum, consistent with the role of Grid2 in Purkinje cell dendrites. Together, these findings establish td as a novel Grid2 mutant mouse model exhibiting cerebellar neurodegeneration.