Novel recessive myotilin mutation causes severe myofibrillar myopathy
Novel recessive myotilin mutation causes severe myofibrillar myopathy
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DOI：
10.1007/s10048-014-0410-4
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发表时间：
2014-08-01
期刊：
影响因子：
2.2
通讯作者：
Schoser, Benedikt
中科院分区：
文献类型：
--
作者：
Schessl, Joachim;Bach, Elisa;Schoser, Benedikt
我们在一个严重肌原纤维性肌病（MFM）的家族中发现了第一个肌球蛋白基因（MYOT）纯合子隐性突变。MFM是一种罕见的、进行性和破坏性的人类骨骼肌疾病，具有明显的蛋白质聚集和肌原纤维变性的组织病理学模式。到目前为止，只有杂合子错义突变MYOT已与常染色体显性肌原纤维肌病，肢带型肌营养不良症1A型和远端肌病。肌动素本身在骨骼肌和心肌中高度表达，并定位于Z盘，因此在肌节组装中相互作用。我们对一个临床诊断为MFM的德国家庭进行了全外显子组测序，并在外显子2中发现了一个纯合突变，c.16C > G（p.Arg6Gly）。使用激光显微切割，然后用定量质谱法，我们确定了肌球蛋白作为一个组成部分，显示最高的增加丰度的聚集在索引患者。我们认为，组合的方法具有很高的潜力，作为一种新的工具，用于确认未分类的变体，发现在全外显子组测序方法。
We identified the first homozygous and hence recessive mutation in the myotilin gene (MYOT) in a family affected by a severe myofibrillar myopathy (MFM). MFM is a rare, progressive and devastating disease of human skeletal muscle with distinct histopathological pattern of protein aggregates and myofibrillar degeneration. So far, only heterozygous missense mutations in MYOT have been associated with autosomal dominant myofibrillar myopathy, limb-girdle muscular dystrophy type 1A and distal myopathy. Myotilin itself is highly expressed in skeletal and cardiac muscle and is localized at the Z-disc and therefore interacts in sarcomere assembly. We performed whole-exome sequencing in a German family clinically diagnosed with MFM and identified a homozygous mutation in exon 2, c.16C > G (p.Arg6Gly). Using laser microdissection followed by quantitative mass spectrometry, we identified the myotilin protein as one component showing the highest increased abundance in the aggregates in the index patient. We suggest that the combined approach has a high potential as a new tool for the confirmation of unclassified variants which are found in whole-exome sequencing approaches.