Embryonic myosin heavy-chain mutations cause distal arthrogryposis and developmental myosin myopathy that persists postnatally
Embryonic myosin heavy-chain mutations cause distal arthrogryposis and developmental myosin myopathy that persists postnatally
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DOI：
10.1001/archneur.65.8.1083
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发表时间：
2008-08-01
影响因子：
--
通讯作者：
Oldfors, Anders
中科院分区：
文献类型：
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作者：
Tajsharghi, Homa;Kimber, Eva;Oldfors, Anders
背景：肌球蛋白是一种分子马达，是横纹肌粗丝的重要组成部分。肌球蛋白重链 (MyHC) 亚型的表达受到发育调节。 MYH3 (OMIM *160720) 编码的胚胎亚型在胎儿生命期间表达。最近，MYH3突变被证明与先天性关节挛缩有关，即Freeman-Sheldon和Sheldon-Hall综合征，这两种综合征都是远端关节挛缩综合征。其他 MyHC 同工型的突变会导致肌病。目前尚不清楚 MYH3 突变是否会导致肌病，因为尚未对肌肉组织进行研究。目的：确定新的 MYH3 突变是否与远端关节弯曲相关，并证明 4 名远端关节弯曲和 MYH3 突变患者的肌肉活检标本中的肌病变化。设计：在一组远端关节弯曲患者中，我们分析了整个编码序列 MYH3 的。获得肌肉活检标本，除了形态学分析外，还研究了蛋白质和转录水平上 MyHC 亚型的表达。结果：我们从 3 个家族中鉴定出具有新 MYH3 突变的患者。这些突变影响位于 MyHC 头部三磷酸腺苷结合口袋不同区域的发育保守残基。在任何肌肉活检样本中均未检测到胚胎 (MYH3) 亚型，表明这些患者中 MYH3 的发育正常下调。然而，4 名患者的肌肉活检标本的形态学分析显示，1 名患者有轻度且多变的肌病特征，胎儿 MyHC 异构体 (MYH8) 病理性上调。结论：与 MYH3 突变相关的远端关节弯曲继发于肌球蛋白肌病，出生后肌肉表现各不相同。
Background: Myosin is a molecular motor and the essential part of the thick filament of striated muscle. The expression of myosin heavy-chain (MyHC) isoforms is developmentally regulated. The embryonic isoform encoded from MYH3 (OMIM *160720) is expressed during fetal life. Recently, mutations in MYH3 were demonstrated to be associated with congenital joint contractures, that is, Freeman-Sheldon and Sheldon-Hall syndromes, which are both distal arthrogryposis syndromes. Mutations in other MyHC isoforms cause myopathy. It is unknown whether MYH3 mutations cause myopathy because muscle tissue has not been studied.Objectives: To determine whether novel MYH3 mutations are associated with distal arthrogryposis and to demonstrate myopathic changes in muscle biopsy specimens from 4 patients with distal arthrogryposis and MYH3 mutations.Design: In a cohort of patients with distal arthrogryposis, we analyzed the entire coding sequence of MYH3. Muscle biopsy specimens were obtained, and in addition to morphologic analysis, the expression of MyHC isoforms was investigated at the protein and transcript levels.Results: We identified patients from 3 families with novel MYH3 mutations. These mutations affect developmentally conserved residues that are located in different regions of the adenosine triphosphate-binding pocket of the MyHC head. The embryonic (MYH3) isoform was not detected in any of the muscle biopsy samples, indicating a normal developmental downregulation of MYH3 in these patients. However, morphologic analysis of muscle biopsy specimens from the 4 patients revealed mild and variable myopathic features and a pathologic upregulation of the fetal MyHC isoform (MYH8) in 1 patient.Conclusions: Distal arthrogryposis associated with MYH3 mutations is secondary to myosin myopathy, and postnatal muscle manifestations are variable.