Novel SIL1 mutations and exclusion of functional candidate genes in Marinesco-Sjogren syndrome
Novel SIL1 mutations and exclusion of functional candidate genes in Marinesco-Sjogren syndrome
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DOI：
10.1038/ejhg.2008.22
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发表时间：
2008-08-01
影响因子：
5.2
通讯作者：
Lehesjoki, Anna-Elina
中科院分区：
文献类型：
--
作者：
Anttonen, Anna-Kaisa;Siintola, Eija;Lehesjoki, Anna-Elina
Marinesco-Sjogren 综合征 (MSS) 是一种罕见的常染色体隐性遗传神经退行性疾病，其特征为小脑性共济失调、白内障、智力低下和进行性肌病。最近，编码内质网 (ER) 驻留辅助伴侣的 SIL1 基因的突变被确定为 MSS 的主要原因。我们在这里报告了 SIL1 的四个新突变，包括 MSS 中描述的第一个错义取代 p.Leu457Pro。此外，我们排除了 HSPA5、HYOU1 和 AARS 三个功能候选基因作为 SIL1 突变阴性患者的致病基因。为了了解 SIL1 功能受到干扰的机制，我们研究了错义突变体 Leu457Pro 蛋白在 COS-1 细胞中的亚细胞定位。此外，我们研究了一种缺乏假定的 C 端 ER 修复信号的突变蛋白。与野生型蛋白定位于内质网和高尔基体相反，两种突变蛋白根据表达水平在内质网内形成聚集体。这些数据表明突变蛋白的聚集可能有助于 MSS 发病机制。 MSS 患者亚组的遗传背景仍不清楚。
Marinesco-Sjogren syndrome (MSS) is a rare autosomal recessively inherited neurodegenerative disorder characterized by cerebellar ataxia, cataracts, mental retardation, and progressive myopathy. Recently, mutations in the SIL1 gene, which encodes an endoplasmic reticulum (ER) resident cochaperone, were identified as a major cause of MSS. We here report four novel mutations in SIL1, including the first missense substitution p.Leu457Pro described in MSS. In addition, we excluded three functional candidate genes, HSPA5, HYOU1, and AARS, as causative genes in SIL1 mutation-negative patients. To understand the mechanisms of disturbed SIL1 function, we studied the subcellular localization of the missense mutant Leu457Pro protein in COS-1 cells. Moreover, we studied a mutant protein lacking the putative C-terminal ER retrieval signal. In contrast to the wild-type protein's localization to ER and Golgi apparatus, both mutant proteins formed aggregates within the ER depending on the expression level. These data imply that aggregation of mutant proteins may contribute to MSS pathogenesis. The genetic background of a subgroup of patients with MSS remains uncovered.