PDF(Pubmed)
Abstract：
Autosomal recessive spastic ataxia in Charlevoix-Saguenay (ARSACS) is a neurodegenerative disorder caused by mutations in the sacsin molecular chaperone protein (SACS) gene. Since the first report from Quebec in 1978, many pathogenic ARSACS variants with significantly reduced chaperone activities have been reported worldwide in adolescents, with presumably altered protein folding. In this study, a novel SACS mutation (p.Val1335IIe, Heterozygous) was identified in a Korean patient in their 50s with late-onset ARSACS characterized by cerebellar ataxia and spasticity without peripheral neuropathy. The mutation was confirmed via whole exome sequencing and Sanger sequencing and was predicted to likely cause disease using prediction software. RT-PCR and ELISA showed decreased SACS mRNA expression and sacsin protein concentrations in the proband, supporting its implications in diseases with pathogenicity and reduced chaperone function from haploinsufficiency. Our results revealed the pathogenicity of the SACS Val1335IIe mutation in the proband patient\'s disease manifestation, even though the symptoms had a limited correlation with the typical ARSACS clinical triad, which could be due to the reduced chaperon function from haploinsufficiency. Furthermore, our study suggests that variants of SACS heterozygosity may have diverse symptoms, with a wide range of disease onsets for late-onset sacsinopathy.
摘要：
Charlevoix-Saguenay（ARSACS）的常染色体隐性遗传性痉挛性共济失调是由sacsin分子伴侣蛋白（SACS）基因突变引起的神经退行性疾病。自1978年魁北克的第一份报告以来，全世界都报道了许多致病性ARSACS变异体，其伴侣活动显着减少，可能有改变的蛋白质折叠。在这项研究中,一种新的SACS突变（p。Val1335IIe,杂合）是在50多岁的韩国患者中发现的，其迟发性ARSACS的特征是小脑共济失调和痉挛，而没有周围神经病变。通过全外显子组测序和Sanger测序确认突变,并使用预测软件预测可能导致疾病。RT-PCR和ELISA显示先证者SACSmRNA表达和sacsin蛋白浓度降低，支持其在具有致病性的疾病中的意义，并由于单倍体不足而降低了伴侣功能。我们的结果揭示了SACSVal1335IIe突变在先证者的疾病表现中的致病性，尽管这些症状与典型的ARSACS临床三联症的相关性有限，这可能是由于单倍体不足导致的伴侣功能降低。此外，我们的研究表明，SACS杂合性的变异可能有不同的症状，迟发性的胰腺病的发病范围很广。
