| A Cypher/ZASP mutation associated with dilated cardiomyopathy alters the binding affinity to protein kinase C. | |
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MedLine Citation:
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PMID: 14660611 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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; Akinori Kimura |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2003-12-03 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 279 ISSN: 0021-9258 ISO Abbreviation: J. Biol. Chem. Publication Date: 2004 Feb |
Date Detail:
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Created Date: 2004-02-17 Completed Date: 2004-04-30 Revised Date: 2013-04-10 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 6746-52 Citation Subset: IM |
Affiliation:
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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. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adaptor Proteins, Signal Transducing Amino Acid Sequence Animals Cardiomyopathy, Dilated / genetics, metabolism* Carrier Proteins / chemistry, genetics* Cytoskeleton / metabolism DNA Mutational Analysis DNA, Complementary / metabolism Female Homeodomain Proteins / chemistry, genetics* Humans LIM Domain Proteins Male Mice Models, Genetic Molecular Sequence Data Mutation Pedigree Plasmids / metabolism Polymorphism, Single-Stranded Conformational Precipitin Tests Protein Binding Protein Isoforms Protein Kinase C / chemistry*, metabolism Protein Structure, Tertiary Rats Reverse Transcriptase Polymerase Chain Reaction Sequence Homology, Amino Acid Signal Transduction Two-Hybrid System Techniques |
| Grant Support | |
ID/Acronym/Agency:
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R01 HL066100/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Adaptor Proteins, Signal Transducing; 0/Carrier Proteins; 0/DNA, Complementary; 0/Homeodomain Proteins; 0/LDB3 protein, human; 0/LIM Domain Proteins; 0/Ldb3 protein, mouse; 0/Protein Isoforms; EC 2.7.11.13/Protein Kinase C |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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