Comparative analysis and functional mapping of SACS mutations reveal novel insights into sacsin repeated architecture.
Comparative analysis and functional mapping of SACS mutations reveal novel insights into sacsin repeated architecture.
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DOI：
10.1002/humu.22269
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发表时间：
2013-03
期刊：
影响因子：
3.9
通讯作者：
Verri, Tiziano
中科院分区：
文献类型：
--
作者：
Romano, Alessandro;Tessa, Alessandra;Barca, Amilcare;Fattori, Fabiana;de Leva, Maria Fulvia;Terracciano, Alessandra;Storelli, Carlo;Santorelli, Filippo Maria;Verri, Tiziano
关键词：
Charlevoix-Saguenay的常染色体隐性痉挛性共济失调（ARSACS）是一种神经系统疾病，SACS突变，编码sacsin，一种4，579个氨基酸的多结构域蛋白。SACS及其翻译蛋白的大尺寸阻碍了对ARSACS的生化分析，并且突变的sacsins如何导致疾病在很大程度上仍然未知。三个重复序列，称为sacsin重复区（SRR）超结构域，已被确认，这有助于sacsin分子伴侣样活性。我们发现这三个SRR比以前描述的大得多（≥ 1，100个残基），并且以离散的亚重复序列组织。我们将大的重复区域命名为Sacsin Internal RePeaTs（SIRPT 1、SIRPT 2和SIRPT 3）和亚重复序列sr 1、sr 2、sr 3和srX。脊椎动物sacsins与一组人类突变的精细定位相结合的比较分析显示，sr 1，sr 2，sr 3和srX是功能性的。值得注意的是，sr 1，sr 2，sr 3和srX中致病性突变的位置似乎与临床表型的严重程度相关，通过定义严重程度评分系统进行评估。我们的结果表明，亚重复序列中突变的相对位置将不同程度地影响sacsin功能障碍。每个重复区域的特定作用的表征将有助于开发一个全面和综合的病理生理学模型的功能sacsin。
Autosomal recessive spastic ataxia of Charlevoix–Saguenay (ARSACS) is a neurological disease with mutations in SACS, encoding sacsin, a multidomain protein of 4,579 amino acids. The large size of SACS and its translated protein has hindered biochemical analysis of ARSACS, and how mutant sacsins lead to disease remains largely unknown. Three repeated sequences, called sacsin repeating region (SRR) supradomains, have been recognized, which contribute to sacsin chaperone-like activity. We found that the three SRRs are much larger (≥1,100 residues) than previously described, and organized in discrete subrepeats. We named the large repeated regions Sacsin Internal RePeaTs (SIRPT1, SIRPT2, and SIRPT3) and the subrepeats sr1, sr2, sr3, and srX. Comparative analysis of vertebrate sacsins in combination with fine positional mapping of a set of human mutations revealed that sr1, sr2, sr3, and srX are functional. Notably, the position of the pathogenic mutations in sr1, sr2, sr3, and srX appeared to be related to the severity of the clinical phenotype, as assessed by defining a severity scoring system. Our results suggest that the relative position of mutations in subrepeats will variably influence sacsin dysfunction. The characterization of the specific role of each repeated region will help in developing a comprehensive and integrated pathophysiological model of function for sacsin.
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