Structural analysis of four and half LIM protein-2 in dilated cardiomyopathy |
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Authors: | 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 |
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Institution: | Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 101-0062, Japan. |
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Abstract: | 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. |
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Keywords: | Dilated cardiomyopathy Four and half LIM protein 2 Titin/connectin Mutation |
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