Slc9a6 mutation causes Purkinje cell loss and ataxia in the shaker rat

The shaker rat carries a naturally occurring mutation leading to progressive ataxia characterized by Purkinje cell (PC) loss. We previously reported on fine-mapping the shaker locus to the long arm of the rat X chromosome. In this work, we sought to identify the mutated gene underlying the shaker phenotype and confirm its identity by functional complementation. We fine-mapped the candidate region and analyzed cerebellar transcriptomes, identifying a XM_217630.9 (Slc9a6):c.[191_195delinsA] variant in the Slc9a6 gene that segregated with disease. We generated an adeno-associated virus (AAV) targeting Slc9a6 expression to PCs using the mouse L7-6 (L7) promoter. We administered the AAV prior to the onset of PC degeneration through intracerebroventricular injection and found that it reduced the shaker motor, molecular and cellular phenotypes. Therefore, Slc9a6 is mutated in shaker and AAV-based gene therapy may be a viable therapeutic strategy for Christianson syndrome, also caused by Slc9a6 mutation.

Automated summary

The shaker rat carries a naturally occurring mutation leading to progressive ataxia characterized by PC loss. In this study, the mutated gene underlying the shaker phenotype was identified as Slc9a6 through fine mapping and transcriptome analysis. It was confirmed that the shaker motor, molecular and cellular phenotypes could be reduced by AAV-based gene therapy targeting Slc9a6 expression. This suggests the potential of AAV-based gene therapy as a viable treatment strategy for Christianson syndrome caused by Slc9a6 mutation.