贝克尔肌营养不良症中肌膜一氧化氮合酶的选择性缺失。
Selective loss of sarcolemmal nitric oxide synthase in Becker muscular dystrophy.
作者信息
Chao D S, Gorospe J R, Brenman J E, Rafael J A, Peters M F, Froehner S C, Hoffman E P, Chamberlain J S, Bredt D S
机构信息
Department of Physiology, University of California at San Francisco School of Medicine 94143-0444, USA.
出版信息
J Exp Med. 1996 Aug 1;184(2):609-18. doi: 10.1084/jem.184.2.609.
Abstract
Becker muscular dystrophy is an X-linked disease due to mutations of the dystrophin gene. We now show that neuronal-type nitric oxide synthase (nNOS), an identified enzyme in the dystrophin complex, is uniquely absent from skeletal muscle plasma membrane in many human Becker patients and in mouse models of dystrophinopathy. An NH2-terminal domain of nNOS directly interacts with alpha 1-syntrophin but not with other proteins in the dystrophin complex analyzed. However, nNOS does not associate with alpha 1-syntrophin on the sarcolemma in transgenic mdx mice expressing truncated dystrophin proteins. This suggests a ternary interaction of nNOS, alpha 1-syntrophin, and the central domain of dystrophin in vivo, a conclusion supported by developmental studies in muscle. These data indicate that proper assembly of the dystrophin complex is dependent upon the structure of the central rodlike domain and have implications for the design of dystrophin-containing vectors for gene therapy.
摘要
贝克尔肌营养不良症是一种由于肌营养不良蛋白基因突变导致的X连锁疾病。我们现在发现，神经元型一氧化氮合酶（nNOS）是肌营养不良蛋白复合物中的一种已确定的酶，在许多人类贝克尔患者和肌营养不良症小鼠模型的骨骼肌质膜中独特地缺失。nNOS的一个NH2末端结构域直接与α1 - 肌养蛋白相互作用，但与所分析的肌营养不良蛋白复合物中的其他蛋白质不相互作用。然而，在表达截短肌营养不良蛋白的转基因mdx小鼠中，nNOS并不与肌膜上的α1 - 肌养蛋白结合。这表明在体内nNOS、α1 - 肌养蛋白和肌营养不良蛋白的中央结构域存在三元相互作用，这一结论得到了肌肉发育研究的支持。这些数据表明，肌营养不良蛋白复合物的正确组装依赖于中央杆状结构域的结构，并对含肌营养不良蛋白的基因治疗载体的设计具有启示意义。
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