Proteomic characterization of aggregate components in an intrafamilial variable FHL1-associated myopathy
Proteomic characterization of aggregate components in an intrafamilial variable FHL1-associated myopathy
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DOI：
10.1016/j.nmd.2013.02.006
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发表时间：
2013-05-01
影响因子：
2.8
通讯作者：
Schessl, Joachim
中科院分区：
文献类型：
--
作者：
Feldkirchner, Sarah;Walter, Maggie C.;Schessl, Joachim
与FHL1突变相关的肌病是罕见的X连锁显性肌纤维性肌病。通过临床检查、组织病理学、Sanger测序和激光显微解剖结合定量质谱仪，我们能够确定两个兄弟的致病基因突变和蛋白聚集体组成，该患者为晚发型X连锁肩周炎-腓骨肌病。疾病的严重进展显示了临床表现的显著的家庭内变异性。肌肉活检中可见蛋白质聚集和还原小体。使用定量质谱仪，我们确定FHL1蛋白是两个患者聚集体中丰度最高的成分，然而，在两个兄弟中，绝对量惊人地不同。此外，我们还在FHL1的第四个LIM结构域中发现了致病的C224W突变。因此，值得注意的是，在两个成年人的肌肉活检中都有明显的小体减少的证据，我们的蛋白质组学数据证实了潜在的基因缺陷，并通过聚集体中总蛋白质含量的比率来确定具有家庭内变异性的潜在基因缺陷。我们认为，我们的联合方法有很高的潜力作为一种新的工具来识别致病基因突变，并提出了蛋白质聚集障碍中可能存在的家庭内变异的线索。由于FHL1基因每个外显子的所有临床亚型和突变都与肌原纤维改变和小体减少有关，我们建议将整个组称为FHL1相关肌病。(C)2013爱思唯尔B.V.保留所有权利。
Myopathies associated with mutations in FHL1 are rare X-linked dominant myofibrillar myopathies. By clinical examination, histopathology, Sanger sequencing, and laser microdissection combined with quantitative mass spectrometry, we were able to identify the causative gene mutation and protein aggregate composition in two brothers with a late-onset X-linked scapulo-axio-peroneal myopathy. The severely progressive course of the disease revealed a remarkable intrafamilial variability of the clinical presentation. Protein aggregation and reducing bodies were observed in the muscle biopsy. Using quantitative mass spectrometry we identified the FHL1 protein as the component showing highest increased abundance in the aggregates in both patients, however, strikingly in a different absolute amount in both brothers. Furthermore, we identified the causative C224W mutation in the fourth LIM-domain of FHL1 in both. Thus, of note is the striking evidence of reducing bodies in the muscle biopsy in both adults, and our proteomic data confirm the underlying gene defect with an intrafamilial variability by the ratio of the total protein content in the aggregates. We suggest that our combined approach has a high potential as a new tool for identification of causative gene mutations and raises hints on possibly intrafamilial variability in protein aggregation disorders. As all clinical subtypes and mutations in each exon of the FHL1 gene are associated with myofibrillar alterations and reducing bodies, we would like to suggest terming the whole group as FHL1-associated myopathies. (C) 2013 Elsevier B.V. All rights reserved.