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J. Biol. Chem., Vol. 279, Issue 8, 6746-6752, February 20, 2004

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A Cypher/ZASP Mutation Associated with Dilated Cardiomyopathy Alters the Binding Affinity to Protein Kinase C^*

Takuro Arimura, Takeharu Hayashi, Hajime Terada¶, Su-Yeoun Lee||**, Qiang Zhou, Megumi Takahashi, Kazuo Ueda, Tatsuhito Nouchi, Shigeru Hohda, Makoto Shibutani, Masao Hirose, Ju Chen, Jeong-Euy Park||, Michio Yasunami, Hideharu Hayashi¶, and Akinori Kimura

From the Department of Molecular Pathogenesis, Medical Research Institute, and Laboratory of Genome Diversity, School of Biomedical Science, Tokyo Medical and Dental University, Tokyo 101-0062, Japan, the Division of Pathology, National Institute of Health Sciences, Tokyo 158-8501, Japan, the ^¶Third Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan, the ^||Division of Cardiology, Samsung Medical Center, Seoul 135-230, Korea, and the Institute of Molecular Medicine and Department of Medicine, University of California at San Diego, La Jolla, California 92093

Dilated cardiomyopathy is characterized by ventricular dilation with systolic dysfunction of cardiac muscle. Recent genetic studies have revealed that mutations in genes for cytoskeleton proteins distributed in the Z-disc and/or intercalated discs of the cardiac muscle are major predictors of cardiomyopathy. However, as mutations in these genes can account for only a part of the patient population, there should be another disease-causing gene(s) for cardiomyopathy. Cypher/ZASP appears to be an ideal candidate for the cardiomyopathy causative gene, because Cypher/ZASP encodes a Z-disc associated protein, and recent studies have demonstrated that Cypher/ZASP knock-out mice develop cardiomyopathy. In this study, we searched for sequence variations in Cypher/ZASP in 96 unrelated Japanese patients with dilated cardiomyopathy. A D626N mutation located within the third LIM domain was identified in a familial case but not found in the unrelated controls. A family study of the patient showed that all affected siblings tested had the same mutation. Clinical information of the affected family members suggested that the mutation was associated with late onset cardiomyopathy. To reveal the biochemical changes due to the mutation, we performed a yeast two-hybrid assay and a pull-down assay. It was demonstrated by both assays that the D626N mutation of Cypher/ZASP increased the affinity of the LIM domain for protein kinase C, suggesting a novel biochemical mechanism of the pathogenesis of dilated cardiomyopathy.

Received for publication, October 29, 2003 , and in revised form, December 2, 2003.

^* This study was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Sports, Culture, Science and Technology of Japan, a research grant from the Ministry of Health and Welfare, Japan, a grant for Japan-Korea collaboration research from Japan Society for the Promotion of Science, and a research grant from Mitsui Life Social Welfare Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** A short-term visiting fellow to the Medical Research Institute, Tokyo Medical and Dental University and supported by a Grant-in-Aid for Scientific Research on Priority Area (C) Medical Genome Science from Ministry of Education, Culture, Sports, Science and Technology, Japan.

To whom correspondence should be addressed: Dept. of Molecular Pathogenesis, Medical Research Inst., Tokyo Medical and Dental University, 2-3-10 Kandasurugadai, Chiyoda-ku, Tokyo 101-0062, Japan. Tel.: 81-3-5280-8056; Fax: 81-3-5280-8055; E-mail: akitis{at}mri.tmd.ac.jp.

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