Department of Basic Medical Sciences, College of Veterinary Medicine, Purdue University, Lynn Hall, 625 Harrison Street, West Lafayette, IN, 47907, USA.
Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN, 55108, USA.
Hum Genet. 2023 Nov;142(11):1587-1601. doi: 10.1007/s00439-023-02599-1. Epub 2023 Sep 27.
ARSACS (autosomal recessive spastic ataxia of Charlevoix-Saguenay) is a human neurological disorder characterized by progressive cerebellar ataxia and peripheral neuropathy. A recently recognized disorder in Great Pyrenees dogs is similarly characterized by widespread central nervous system degeneration leading to progressive cerebellar ataxia and spasticity, combined with peripheral neuropathy. Onset of clinical signs occurred in puppies as young as 4 months of age, with slow progression over several years. A multi-generation pedigree suggested an autosomal recessive mode of inheritance. 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 Mb region on CFA25 in which all cases were homozygous and all controls were either heterozygous or homozygous for alternate haplotypes. This region tagged the SACS gene where variants are known to cause ARSACS. Sanger sequencing of SACS in affected dogs identified a 4 bp 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.
ARSACS（夏洛瓦-萨格奈脑脊髓共济失调，常染色体隐性遗传）是一种人类神经疾病，其特征为进行性小脑共济失调和周围神经病。最近在大比利牛斯犬中发现的一种类似疾病也具有广泛的中枢神经系统退行性变，导致进行性小脑共济失调和痉挛，并伴有周围神经病。临床症状在 4 月龄以下的幼犬中出现，经过数年的缓慢进展。一个多代系谱提示常染色体隐性遗传模式。组织病理学显示一致的小脑浦肯野细胞退化、脑干核神经元退化、广泛的脊髓白质退化、神经节细胞退化、不适当的薄髓鞘或完全脱髓鞘的周围神经纤维，以及骨骼肌正常或仅轻度失神经萎缩模式。从 6 个病例和 26 个对照中收集了全基因组单核苷酸多态性 (SNP) 基因型数据，其中纯合子作图确定了 CFA25 上的 3.3 Mb 区域，所有病例均为纯合子，所有对照均为杂合子或 alternate haplotypes 的纯合子。该区域标记了 SACS 基因，已知该基因的变体可导致 ARSACS。受影响犬的 SACS 基因的 Sanger 测序确定了一个 4 bp 的缺失，导致移码和截断编码 sacsin 蛋白的 C 末端的 343 个氨基酸 (p.Val4244AlafsTer32)。我们对这种犬类疾病的临床和组织病理学描述有助于 ARSACS 的描述，并代表了这种疾病的第一个自然发生的大型动物模型。
