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

Figueroa, K. P.; Anderson, C. J.; Paul, S.; Dansithong, W.; Gandelman, M. M.; Scoles, D. R.; Pulst, S. M.

doi:10.1101/2022.03.28.486143

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bioRxiv · 10.1101/2022.03.28.486143

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

Figueroa, K. P.·Anderson, C. J.·Paul, S.·Dansithong, W.·Gandelman, M. M.·Scoles, D. R.·Pulst, S. M.

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Abstract

BackgroundThe 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. MethodsWe fine-mapped the candidate region and analyzed cerebellar transcriptomes to identify deleterious variants. We generated an adeno-associated virus (AAV) targeting solute carrier family 9, member A6 (Slc9a6) expression to PCs using a mouse L7-6 (L7) promoter, as well as a control green fluorescent protein (GFP)-expressing virus. We administered AAVs prior to the onset of PC degeneration through intracerebroventricular injection and evaluated the molecular, cellular, and motor phenotypes. ResultsWe identified a XM_217630.9 (Slc9a6):c.[191_195delinsA] variant in the Slc9a6 gene that segregated with disease. This mutation is predicted to generate a truncated sodium-hydrogen exchanger 6 (NHE6) protein, p.(Ala64Glufs*23). Administration of AAV9-PHP.eB expressing rat Slc9a6 prior to symptom onset reduced the shaker motor, molecular, and cellular phenotypes. InterpretationSlc9a6 is mutated in shaker and also in human Christianson syndrome, an epileptic encephalopathy. AAV-based gene therapy may be a viable therapeutic strategy for Christianson syndrome, and the shaker rat model may aid in therapeutic development.

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Figueroa, K. P., Anderson, C. J., Paul, S., Dansithong, W., Gandelman, M. M., Scoles, D. R., Pulst, S. M.. 2022-03-29. Slc9a6 mutation causes Purkinje cell loss and ataxia in the spontaneous shaker rat. https://doi.org/10.1101/2022.03.28.486143

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