Department of Medical Genetics, Tohoku University School of Medicine, Sendai, Japan.
J Hum Genet. 2013 May;58(5):259-66. doi: 10.1038/jhg.2013.9. Epub 2013 Feb 28.
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.
肌纤维病（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性细胞质体肌病，现在已被纳入 MFM，其特征为晚发性慢性进行性远端肌肉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，发现了 TTN 基因中的一个新的 c.90263G>T 突变（NM_001256850）。在我们的研究过程中，另一个研究小组报道了 TTN 中的三个突变与遗传性早发性呼吸衰竭相关的肌病（HMERF，MIM #603689）有关，该疾病的病理表现与 MFM 重叠。我们的患者在临床上与 HMERF 相符合。本研究中发现的突变和 HMERF 患者中的三个突变都位于肌联蛋白的 A 带结构域，提示肌联蛋白 A 带结构域的突变与 HMERF 之间存在很强的关系。由于 TTN 基因巨大，包含 363 个外显子，因此很少进行 TTN 的突变筛查。有可能对 TTN 进行有针对性的分析，可以在 MFM 患者中发现更多的突变，尤其是在那些有早期呼吸衰竭的患者中。
