Department of Biology, University of Padova, Padova, Italy.
Eur J Neurol. 2013 Nov;20(11):1486-91. doi: 10.1111/ene.12220. Epub 2013 Jun 25.
Mutations in the SACS gene are commonly associated with autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), a complex neurodegenerative disorder characterized by progressive degeneration of the cerebellum and spinal cord tracts. The aim of this study was to identify the genetic cause of the disease in an Italian family with spastic paraplegia and peripheral neuropathy.
Affected subjects were subjected to a comprehensive neurological examination including electromyography and brain magnetic resonance imaging. Genetic studies included exclusion of known disease genes, genome-wide linkage analysis using high density single nucleotide polymorphism genotyping and candidate gene sequencing.
Molecular analyses revealed a novel missense mutation in the SACS gene (c.11,104A>G) occurring in a homozygous state in patients and absent in 700 Italian control chromosomes. The mutation led to the amino acid substitution p.Thr3702Ala in the sacsin protein, in a possible protein-protein interaction site of UBE3A binding domain.
This study broadens the genetic spectrum of SACS mutations and expands the clinical ARSACS phenotype suggesting that the SACS gene can be considered in patients with non-canonical ARSACS clinical presentations.
SACS 基因突变通常与常染色体隐性痉挛性共济失调（ARSACS）有关，这是一种复杂的神经退行性疾病，其特征是小脑和脊髓束进行性退化。本研究的目的是在一个具有痉挛性截瘫和周围神经病的意大利家族中确定该疾病的遗传原因。
受影响的受试者接受了全面的神经系统检查，包括肌电图和脑磁共振成像。遗传研究包括排除已知疾病基因、使用高密度单核苷酸多态性基因分型的全基因组连锁分析和候选基因测序。
分子分析显示 SACS 基因（c.11,104A>G）中的一个新的错义突变在患者中呈纯合状态，而在 700 个意大利对照染色体中不存在。该突变导致 sacsin 蛋白中的氨基酸取代 p.Thr3702Ala，这可能是 UBE3A 结合域的蛋白质-蛋白质相互作用位点。
本研究拓宽了 SACS 基因突变的遗传谱，并扩展了 ARSACS 的临床表型，提示在具有非典型 ARSACS 临床表现的患者中可以考虑 SACS 基因。
