Arimura Takuro, Hayashi Takeharu, Matsumoto Yuji, Shibata Hiroki, Hiroi Shitoshi, Nakamura Takeyuki, Inagaki Natsuko, Hinohara Kunihiko, Takahashi Megumi, Manatsu Satoh-Itoh, Sasaoka Taishi, Izumi Toru, Bonne Gisèle, Schwartz Ketty, Kimura Akinori
Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 101-0062, Japan.
Biochem Biophys Res Commun. 2007 May 25;357(1):162-7. doi: 10.1016/j.bbrc.2007.03.128. Epub 2007 Mar 30.
Dilated cardiomyopathy (DCM) is a cardiac disease characterized by dilated ventricle and systolic dysfunction. Most of the DCM patients are sporadic cases, but a certain population of DCM patients can be familial cases caused by mutations in genes for sarcomere/Z-disc components including titin/connectin. However, disease-causing mutations could be identified only in a part of the familial DCM patients, suggesting that there should be other disease causing genes for DCM. To explore a novel disease gene for DCM, we searched for mutations in FHL2, encoding for four and half LIM protein 2 (FHL2) in DCM patients, because FHL2 is known to associate with titin/connectin. A missense mutation, Gly48Ser, was identified in a patient with familial DCM. Functional analysis demonstrated that the FHL2 mutation affected the binding to titin/connectin. Because FHL2 protein is known to tether metabolic enzymes to titin/connectin, these observations suggest that the Gly48Ser mutation may be involved in the pathogenesis of DCM via impaired recruitment of metabolic enzymes to the sarcomere.
扩张型心肌病（DCM）是一种以心室扩张和收缩功能障碍为特征的心脏疾病。大多数DCM患者为散发病例，但有一定比例的DCM患者为家族性病例，由肌节/Z盘成分（包括肌联蛋白/连接蛋白）的基因突变引起。然而，仅在部分家族性DCM患者中可鉴定出致病突变，这表明DCM应该还有其他致病基因。为了探索DCM的新致病基因，我们在DCM患者中寻找编码四半LIM蛋白2（FHL2）的FHL2基因中的突变，因为已知FHL2与肌联蛋白/连接蛋白相关。在一名家族性DCM患者中鉴定出一个错义突变Gly48Ser。功能分析表明，FHL2突变影响其与肌联蛋白/连接蛋白的结合。由于已知FHL2蛋白可将代谢酶与肌联蛋白/连接蛋白相连，这些观察结果提示，Gly48Ser突变可能通过损害代谢酶向肌节的募集而参与DCM的发病机制。
