SIL1 mutations and clinical spectrum in patients with Marinesco-Sjogren syndrome
SIL1 mutations and clinical spectrum in patients with Marinesco-Sjogren syndrome
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DOI：
10.1093/brain/awt283
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发表时间：
2013-12-01
期刊：
影响因子：
14.5
通讯作者：
Senderek, Jan
中科院分区：
文献类型：
--
作者：
Krieger, Michael;Roos, Andreas;Senderek, Jan
Marinesco-Sjogren 综合征是一种罕见的常染色体隐性多系统疾病，以小脑共济失调、早发性白内障、慢性肌病、不同程度的智力障碍和运动发育迟缓为特征。最近，编码内质网驻留共伴侣的 SIL1 基因的突变被确定为 Marinesco-Sjogren 综合征的主要原因。在这里，我们描述了 62 名患有早发性共济失调、白内障和肌病或其中至少两种的组合的患者的 SIL1 突变分析结果。我们在具有特征性 Marinesco-Sjogren 综合征三联征（共济失调、白内障、肌病）的患者中获得了 60% (15/25) 的突变检出率，而表型表现变化较大的患者组中的突变检出率低于 3% (1/37)。我们报告了 16 个不相关的家族，总共有 19 种不同的 SIL1 突变。这些突变中有 15 种以前未报告的变化，包括单外显子和多外显子缺失。根据我们筛选队列的数据和文献汇编的数据，我们发现 SIL1 突变总是与小脑综合征和慢性肌病的组合相关。在 7 岁以上的所有患者中均观察到白内障，但在婴儿中可能缺失。六名携带 SIL1 突变的患者没有智力障碍，这将 Marinesco-Sjogren 综合征的已知认知能力范围扩大到了正常智力。适度恒定的特征是体细胞生长迟缓、骨骼异常和锥体束征。对培养的患者淋巴母细胞中突变型 SIL1 表达的检查表明，无论突变的类型和位置如何，SIL1 突变都会导致 SIL1 蛋白水平严重降低。我们的数据拓宽了 SIL1 突变谱并证实 SIL1 是主要的 Marinesco-Sjogren 综合征基因。 SIL1 患者通常表现为特征性三联征，但幼儿可能没有白内障。由于认知障碍不是强制性的，因此没有智力障碍但具有 Marinesco-Sjogren 综合征相容表型的患者应接受 SIL1 突变分析。尽管存在等位基因异质性并且许多家族具有私人突变，但与 SIL1 突变相关的表型相对同质。基于 SIL1 表达研究，我们推测这可能是由于不同突变对蛋白质表达的一致影响所致。
Marinesco-Sjogren syndrome is a rare autosomal recessive multisystem disorder featuring cerebellar ataxia, early-onset cataracts, chronic myopathy, variable intellectual disability and delayed motor development. More recently, mutations in the SIL1 gene, which encodes an endoplasmic reticulum resident co-chaperone, were identified as the main cause of Marinesco-Sjogren syndrome. Here we describe the results of SIL1 mutation analysis in 62 patients presenting with early-onset ataxia, cataracts and myopathy or combinations of at least two of these. We obtained a mutation detection rate of 60% (15/25) among patients with the characteristic Marinesco-Sjogren syndrome triad (ataxia, cataracts, myopathy) whereas the detection rate in the group of patients with more variable phenotypic presentation was below 3% (1/37). We report 16 unrelated families with a total of 19 different SIL1 mutations. Among these mutations are 15 previously unreported changes, including single- and multi-exon deletions. Based on data from our screening cohort and data compiled from the literature we found that SIL1 mutations are invariably associated with the combination of a cerebellar syndrome and chronic myopathy. Cataracts were observed in all patients beyond the age of 7 years, but might be missing in infants. Six patients with SIL1 mutations had no intellectual disability, extending the known wide range of cognitive capabilities in Marinesco-Sjogren syndrome to include normal intelligence. Modestly constant features were somatic growth retardation, skeletal abnormalities and pyramidal tract signs. Examination of mutant SIL1 expression in cultured patient lymphoblasts suggested that SIL1 mutations result in severely reduced SIL1 protein levels irrespective of the type and position of mutations. Our data broaden the SIL1 mutation spectrum and confirm that SIL1 is the major Marinesco-Sjogren syndrome gene. SIL1 patients usually present with the characteristic triad but cataracts might be missing in young children. As cognitive impairment is not obligatory, patients without intellectual disability but a Marinesco-Sjogren syndrome-compatible phenotype should receive SIL1 mutation analysis. Despite allelic heterogeneity and many families with private mutations, the phenotype related to SIL1 mutations is relatively homogenous. Based on SIL1 expression studies we speculate that this may arise from a uniform effect of different mutations on protein expression.