We show here the utility of investigating spontaneous mouse mutations in understanding human disease. Currently, the small number of aged Itpr1wt/Δ18 animals precludes us from examining these mice for subtle signs and symptoms similar to those seen in SCA15 patients; however, these mice are clearly of interest to us as a potential model of SCA15. These data also demonstrate that genome-wide SNP assay can facilitate rapid detection of structural genomic mutations that may underlie disease. The data provided by these approaches provide compelling evidence that heterozygous deletion of ITPR1 causes SCA15. Clearly, sequence analysis of ITPR1 in potential SCA15 cases may provide additional insight into the disease, particularly if a stop mutation were to be identified; however, the mutational mechanism noted here means that standard sequencing approaches alone are insufficient to confidently rule out ITPR1 mutation as a cause of disease: a comprehensive gene dosage approach is also required. Given that SCA16 and autosomal dominant congenital nonprogressive ataxia have both recently been mapped to regions overlapping with the SCA15 locus [10,11], ITPR1 is a gene of importance for screening in these families. These data add weight to a role for aberrant intracellular Ca2+ signaling in Purkinje cells in the pathogenesis of spinocerebellar ataxia.