Hotfoot Mouse Mutations Affect the δ2 Glutamate Receptor Gene and Are Allelic to Lurcher

Hotfoot (ho) is a recessive mouse mutation characterized by cerebellar ataxia associated with relatively mild abnormalities of the cerebellum. It has been previously mapped to Chromosome 6, and at least eight independent alleles have been reported. Here we show that the hotfoot phenotype is associated with mutations in the glutamate receptor ionotropic δ2 gene (Grid2). We have identified a 510-bp deletion in theGrid2coding sequence in theho4Jallele, resulting in a deletion of 170 amino acids of the extracellular domain of the receptor. Analysis of a second allele,hoTgN37INRA, revealed a 4-kb deletion in theGrid2transcript. The GRID2 protein in these hotfoot mutants probably has a reduced (or null) activity since the phenotype of hotfoot bears similarities with the previously described phenotype ofGrid2knockout mice. The exceptionally high number of independent alleles at theholocus is an invaluable tool for investigating the function of the glutamate receptor ionotropic δ2 protein, which so far remains largely unknown.