Conspicuous involvement of desmin tail mutations in diverse cardiac and skeletal myopathies
Conspicuous involvement of desmin tail mutations in diverse cardiac and skeletal myopathies
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DOI：
10.1002/humu.20459
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发表时间：
2007-04-01
期刊：
影响因子：
3.9
通讯作者：
Herrmann, Harald
中科院分区：
文献类型：
--
作者：
Bar, Harald;Goudeau, Bertrand;Herrmann, Harald
肌原纤维性肌病（MFM）包括一组由编码肌肉结构蛋白的基因突变引起的遗传异质性人类疾病。中间丝（IF）蛋白结蛋白（DES）（肌细胞的主要细胞骨架组分）的突变导致严重形式的“结蛋白病”，其影响心脏、骨骼肌和平滑肌。所描述的大多数突变位于结蛋白的中央（X，螺旋杆结构域）。在这里，我们报告了三个新的突变-c.1325C> T（p.T4421），c.1360C > T（p.R454W）和c.1379G > T（p.S4601）-位于结蛋白的非，α-螺旋羧基末端“尾”结构域。我们已经研究了这些和四个c.1237G> A（p.E413K）、c.1346A > C（p.K449T）、c.1353C > G（p.1451M）和c.1405G > A（p.V469M）--先前描述的“尾”突变对体外细丝形成和转染成肌细胞中有序细胞骨架阵列的产生的影响。尽管除了两个突变体（p.E413K，p.R454W）之外的所有突变体在体外组装成IF，并且除了p.E413K之外的所有突变体在转染的C2 C12细胞中被并入IF阵列中，但是如粘度组装测定所揭示的，丝特性与野生型结蛋白显著不同。最值得注意的是，当与野生型结蛋白共组装时，这些突变体揭示了对纤维形成能力和纤维-细丝相互作用的严重干扰，表明突变体和野生型蛋白质形成混合细丝的固有不相容性。观察到的各种临床表型可能反映了结蛋白尾部结构域与成肌细胞细胞骨架不同组分的相互作用改变，导致生物力学特性降低和/或个体肌细胞代谢改变。我们的体外组装方案被证明是一个非常明智的工具，以检测如果一个特定的结蛋白突变能够导致丝异常。
Myofibrillar myopathy (MFM) encompasses a genetically heterogeneous group of human diseases caused by mutations in genes coding for structural proteins of muscle. Mutations in the intermediate filament (IF) protein desmin (DES), a major cytoskeletal component of myocytes, lead to severe forms of "desminopathy," which affects cardiac, Skeletal, and smooth muscle. Most mutations described reside in the central (X,helical rod domain of desmin. Here we report three novel mutations-c.1325C > T (p.T4421), c.1360C > T (p.R454W), and c.1379G > T (p.S4601)-located in desmin's non,a-helical carboxy-terminal "tail" domain. We have investigated the impact of these and four-c.1237G > A (p.E413K), C.1346A > C (p.K449T), c.1353C > G (p.1451M), and c.1405G > A (p.V469M) -previously described "tail" mutations on in vitro filament formation and on the generation of ordered cytoskeletal arrays in transfected myoblasts. Although all but two mutants (p.E413K, p.R454W) assembled into IFs in vitro and all except p.E413K were incorporated into IF arrays in transfected C2C12 cells, filament properties differed significantly from wild,type desmin as revealed by viscometric assembly assays. Most notably, when coassembled with wild-type desmin, these mutants revealed a severe disturbance of filament-formation competence and filament-filament interactions, indicating an inherent incompatibility of mutant and wild,type protein to form mixed filaments. The various clinical phenotypes observed may reflect altered interactions of desmin's tail domain with different components of the myoblast cytoskeleton leading to diminished biomechanical properties and/or altered metabolism of the individual myocyte. Our in vitro assembly regimen proved to be a very sensible tool to detect if a particular desmin mutation is able to cause filament abnormalities.