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Histopathology revealed consistent cerebellar Purkinje cell degeneration, neuronal degeneration in brainstem nuclei, widespread spinal cord white matter degeneration, ganglion cell degeneration, inappropriately thin myelin sheaths or fully demyelinated peripheral nerve fibers, and normal or only mild patterns of denervation atrophy in skeletal muscles. Genome-wide single nucleotide polymorphism (SNP) genotype data was collected from 6 cases and 26 controls, where homozygosity mapping identified a 3.3\u00a0Mb region on CFA25 in which all cases were homozygous and all controls were either heterozygous or homozygous for alternate haplotypes. This region tagged the <jats:italic>SACS<\/jats:italic> gene where variants are known to cause ARSACS. Sanger sequencing of <jats:italic>SACS<\/jats:italic> in affected dogs identified a 4\u00a0bp deletion that causes a frame shift and truncates 343 amino acids from the C terminus of the encoded sacsin protein (p.Val4244AlafsTer32). Our clinical and histopathological descriptions of this canine disorder contribute to the description of human ARSACS and represents the first naturally occurring large animal model of this disorder.<\/jats:p>","DOI":"10.1007\/s00439-023-02599-1","type":"journal-article","created":{"date-parts":[[2023,9,27]],"date-time":"2023-09-27T20:27:04Z","timestamp":1695846424000},"page":"1587-1601","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A SACS deletion variant in Great Pyrenees dogs causes autosomal recessive neuronal degeneration"],"prefix":"10.1007","volume":"142","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3213-7883","authenticated-orcid":false,"given":"Kari J.","family":"Ekenstedt","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5472-5088","authenticated-orcid":false,"given":"Katie M.","family":"Minor","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3332-1359","authenticated-orcid":false,"given":"G. 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