C-terminal titin deletions cause a novel early-onset myopathy with fatal cardiomyopathy
C-terminal titin deletions cause a novel early-onset myopathy with fatal cardiomyopathy
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DOI：
10.1002/ana.21089
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发表时间：
2007-04-01
影响因子：
11.2
通讯作者：
Ferreiro, Ana
中科院分区：
文献类型：
--
作者：
Carmignac, Virginie;Salih, Mustafa A. M.;Ferreiro, Ana
目的：肌联蛋白是横纹肌发育、结构和弹性所必需的蛋白质。迄今为止报道的所有肌联蛋白突变均引起迟发性显性疾病，涉及骨骼肌或心脏。我们的目的是描绘的表型，并确定遗传缺陷的两个血缘家庭的早发性，隐性肌肉和心脏disorder.Methods：临床和myopathological重新评估的五个受影响的儿童，位置克隆，免疫荧光，和Western blot studywerperformed.Results：所有的孩子都提出了先天性肌无力和儿童发病的致命性扩张型心肌病。骨骼肌活检显示小核心，位于中央的核，和/或营养不良病变。在每个家庭中，我们确定了一个纯合肌联蛋白缺失外显子编码的C-末端M-线区域。这两种缺失都会导致肌联蛋白激酶结构域下游的移码和蛋白质截短。免疫荧光证实，截短titins缺乏C-末端纳入肌节。钙蛋白酶3是次要depleted.Interpretation：M-线肌联蛋白纯合子截断导致第一个先天性和纯隐性肌联蛋白病，第一个涉及心脏和骨骼肌。这些结果扩大了早发性肌病的范围，并表明肌联蛋白片段下游的激酶结构域是骨骼肌和心肌发育的关键，但对维持肌节的完整性至关重要。
Objective: The giant protein titin is essential for striated muscle development, structure, and elasticity. All titin mutations reported to date cause late-onset, dominant disorders involving either skeletal muscle or the heart. Our aim was to delineate the phenotype and determine the genetic defects in two consanguineous families with an early-onset, recessive muscle and cardiac disorder.Methods: Clinical and myopathological reevaluation of the five affected children, positional cloning, immunofluorescence, and Western blot studies were performed.Results: All children presented with congenital muscle weakness and childhood-onset fatal dilated cardiomyopathy. Skeletal muscle biopsies showed minicores, centrally located nuclei, and/or dystrophic lesions. In each family, we identified a homozygous titin deletion in exons encoding the C-terminal M-line region. Both deletions cause a frameshift downstream of the titin kinase domain and protein truncation. Immunofluorescence confirmed that truncated titins lacking the C-terminal end were incorporated into sarcomeres. Calpain 3 was secondarily depleted.Interpretation: M-line titin homozygous truncations cause the first congenital and purely recessive titinopathy, and the first to involve both cardiac and skeletal muscle. These results expand the spectrum of early-onset myopathies and suggest that titin segments downstream of the kinase domain are dispensable for skeletal and cardiac muscle development, but are crucial for maintaining sarcomere integrity.