Truncation by Glu180 nonsense mutation results in complete loss of slow skeletal muscle troponin T in a lethal nemaline myopathy
Truncation by Glu180 nonsense mutation results in complete loss of slow skeletal muscle troponin T in a lethal nemaline myopathy
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DOI：
10.1074/jbc.m303469200
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发表时间：
2003-07-11
影响因子：
4.8
通讯作者：
Crawford, TO
中科院分区：
文献类型：
--
作者：
Jin, JP;Brotto, MA;Crawford, TO
一种致命的线状肌病，称为“阿米什线状肌病”(ANM)，与慢骨骼肌肌钙蛋白 T (TnT) 基因中密码子 Glu(180) 的无义突变有关。我们发现 ANM 患者的肌肉中既不存在完整的慢 TnT 蛋白，也不存在截短的慢 TnT 蛋白。慢 TnT 的完全丧失与观察到的疾病遗传隐性模式一致，表明 COOH 末端 T2 结构域在 TnT 整合到肌原纤维中的关键作用。 TnT 慢速和快速亚型的表达具有纤维类型特异性。缺乏慢 TnT 会导致 1 型纤维选择性萎缩。在单纤维收缩力测定中，慢速 TnT 比快速 TnT 具有更高的 Ca2+ 敏感性。尽管缺乏慢 TnT，ANM 患者出生时肌肉力量正常。 ANM 的出生后发病和婴儿期进展与正常发育的人类骨骼肌中快速 TnT 的心脏和胚胎剪接变体的下调相对应，表明胎儿 TnT 亚型补充了慢速 TnT。这些结果为理解 ANM 的分子病理生理学和潜在的靶向治疗奠定了基础。
A lethal form of nemaline myopathy, named "Amish Nemaline Myopathy" (ANM), is linked to a nonsense mutation at codon Glu(180) in the slow skeletal muscle troponin T (TnT) gene. We found that neither the intact nor the truncated slow TnT protein was present in the muscle of patients with ANM. The complete loss of slow TnT is consistent with the observed recessive pattern of inheritance of the disease and indicates a critical role of the COOH-terminal T2 domain in the integration of TnT into myofibrils. Expression of slow and fast isoforms of TnT is fiber-type specific. The lack of slow TnT results in selective atrophy of type 1 fibers. Slow TnT confers a higher Ca2+ sensitivity than does fast TnT in single fiber contractility assays. Despite the lack of slow TnT, individuals with ANM have normal muscle power at birth. The postnatal onset and infantile progression of ANM correspond to a down-regulation of cardiac and embryonic splice variants of fast TnT in normal developing human skeletal muscle, suggesting that the fetal TnT isoforms complement slow TnT. These results lay the foundation for understanding the molecular pathophysiology and the potential targeted therapy of ANM.