MYBPC1 mutations impair skeletal muscle function in zebrafish models of arthrogryposis
MYBPC1 mutations impair skeletal muscle function in zebrafish models of arthrogryposis
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DOI：
10.1093/hmg/ddt344
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发表时间：
2013-12-15
影响因子：
3.5
通讯作者：
Gurnett, Christina A.
中科院分区：
文献类型：
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作者：
Ha, Kyungsoo;Buchan, Jillian G.;Gurnett, Christina A.
肌球蛋白结合蛋白 C1 (MYBPC1) 是一种丰富的骨骼肌蛋白，主要在慢肌纤维中表达。人类 MYBPC1 突变与 1 型远端关节挛缩症和 4 型致死性先天性挛缩综合征相关。由于 MYBPC1 功能尚不完全清楚，人类突变导致挛缩的机制尚不清楚。在这里，我们使用反义吗啉敲低证明，mybpc1 是斑马鱼关节弯曲模型中胚胎运动活动和存活所必需的。 Mybpc1 变形胚胎具有严重的身体弯曲、心源性水肿、运动兴奋受损且孵化延迟。尽管电子显微镜显示正常的肌节结构，但慢骨骼肌中的肌原纤维组织选择性受损，并且 mybpc1 敲低胚胎中的肌节数量大大减少。为了评估人类远端关节弯曲突变的影响，将含有相应人类 W236R 和 Y856H MYBPC1 突变的 mybpc1 mRNA 注射到胚胎中。与野生型 RNA 的过度表达相比，这些突变的显性负面影响是由所产生的轻微弯曲的身体弯曲、运动活动减少以及总体生存受损组成的。这些结果证明了 mybpc1 在骨骼肌发育缓慢中的关键作用，并将斑马鱼确立为人类远端关节弯曲的易处理模型。
Myosin-binding protein C1(MYBPC1) is an abundant skeletal muscle protein that is expressed predominantly in slow-twitch muscle fibers. Human MYBPC1 mutations are associated with distal arthrogryposis type 1 and lethal congenital contracture syndrome type 4. As MYBPC1 function is incompletely understood, the mechanism by which human mutations result in contractures is unknown. Here, we demonstrate using antisense morpholino knockdown, that mybpc1 is required for embryonic motor activity and survival in a zebrafish model of arthrogryposis. Mybpc1 morphant embryos have severe body curvature, cardiac edema, impaired motor excitation and are delayed in hatching. Myofibril organization is selectively impaired in slow skeletal muscle and sarcomere numbers are greatly reduced in mybpc1 knockdown embryos, although electron microscopy reveals normal sarcomere structure. To evaluate the effects of human distal arthrogryposis mutations, mybpc1 mRNAs containing the corresponding human W236R and Y856H MYBPC1 mutations were injected into embryos. Dominant-negative effects of these mutations were suggested by the resultant mild bent body curvature, decreased motor activity, as well as impaired overall survival compared with overexpression of wild-type RNA. These results demonstrate a critical role for mybpc1 in slow skeletal muscle development and establish zebrafish as a tractable model of human distal arthrogryposis.