Exome sequencing identifies a novel TTN mutation in a family with hereditary myopathy with early respiratory failure
Exome sequencing identifies a novel TTN mutation in a family with hereditary myopathy with early respiratory failure
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DOI：
10.1038/jhg.2013.9
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发表时间：
2013-05-01
影响因子：
3.5
通讯作者：
Matsubara, Yoichi
中科院分区：
文献类型：
--
作者：
Izumi, Rumiko;Niihori, Tetsuya;Matsubara, Yoichi
肌原纤维性肌病（MFM）是一组慢性肌肉疾病，表现为肌原纤维的局灶性溶解和降解产物的积累。MFMs的主要遗传基础尚不清楚。1993年，我们的研究小组报道了一个日本家族，该家族主要遗传细胞质体肌病，现在被纳入MFM，其特征是迟发性慢性进行性远端肌无力和早期呼吸衰竭。在这项研究中，我们对这些患者进行了连锁分析和外显子组测序，并在TTN基因（NM_001256850）中发现了一个新的c. 90263G>T突变。在我们的研究过程中，另一组报告了遗传性肌病伴早期呼吸衰竭患者（HMERF, MIM #603689）中TTN的三个突变，其特征是与mfm的病理发现重叠。我们的患者在临床上与HMERF兼容。本研究中发现的突变和HMERF患者的三个突变都位于titin的a带结构域，提示titin的a带结构域突变与HMERF之间存在较强的关系。由于TTN由363个外显子组成，体积庞大，因此很少进行突变筛选。TTN的集中分析可能会在mfm患者中发现更多的突变，特别是在早期呼吸衰竭患者中。
Myofibrillar myopathy (MFM) is a group of chronic muscular disorders that show the focal dissolution of myofibrils and accumulation of degradation products. The major genetic basis of MFMs is unknown. In 1993, our group reported a Japanese family with dominantly inherited cytoplasmic body myopathy, which is now included in MFM, characterized by late-onset chronic progressive distal muscle weakness and early respiratory failure. In this study, we performed linkage analysis and exome sequencing on these patients and identified a novel c. 90263G>T mutation in the TTN gene (NM_001256850). During the course of our study, another groups reported three mutations in TTN in patients with hereditary myopathy with early respiratory failure (HMERF, MIM #603689), which is characterized by overlapping pathologic findings with MFMs. Our patients were clinically compatible with HMERF. The mutation identified in this study and the three mutations in patients with HMERF were located on the A-band domain of titin, suggesting a strong relationship between mutations in the A-band domain of titin and HMERF. Mutation screening of TTN has been rarely carried out because of its huge size, consisting of 363 exons. It is possible that focused analysis of TTN may detect more mutations in patients with MFMs, especially in those with early respiratory failure.