Tajsharghi Homa, Kimber Eva, Kroksmark Anna-Karin, Jerre Ragnar, Tulinius Mar, Oldfors Anders
Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
Arch Neurol. 2008 Aug;65(8):1083-90. doi: 10.1001/archneur.65.8.1083.
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.
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.
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.
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.
Distal arthrogryposis associated with MYH3 mutations is secondary to myosin myopathy, and postnatal muscle manifestations are variable.
肌球蛋白是一种分子马达，是横纹肌粗肌丝的重要组成部分。肌球蛋白重链（MyHC）亚型的表达受发育调控。由MYH3（OMIM *160720）编码的胚胎亚型在胎儿期表达。最近，已证明MYH3突变与先天性关节挛缩有关，即弗里曼-谢尔顿综合征和谢尔顿-霍尔综合征，这两种都是远端关节弯曲综合征。其他MyHC亚型的突变会导致肌病。由于尚未对肌肉组织进行研究，因此尚不清楚MYH3突变是否会导致肌病。
确定新的MYH3突变是否与远端关节弯曲有关，并证明4例患有远端关节弯曲和MYH3突变的患者肌肉活检标本中的肌病变化。
在一组远端关节弯曲患者中，我们分析了MYH3的整个编码序列。获取肌肉活检标本，除了进行形态学分析外，还在蛋白质和转录水平上研究MyHC亚型的表达。
我们在3个家族中鉴定出患有新的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的发育下调正常。然而，对4例患者的肌肉活检标本进行的形态学分析显示，有轻度且可变的肌病特征，并且1例患者中胎儿MyHC亚型（MYH8）出现病理性上调。
与MYH3突变相关的远端关节弯曲继发于肌球蛋白肌病，出生后肌肉表现各异。
