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A Cypher/ZASP mutation associated with dilated cardiomyopathy alters the binding affinity to protein kinase C.

Authors: Arimura, T  Hayashi, T  Terada, H  Lee, SY  Zhou, Q  Takahashi, M  Ueda, K  Nouchi, T  Hohda, S  Shibutani, M  Hirose, M  Chen, J  Park, JE  Yasunami, M  Hayashi, H  Kimura, A 
Citation: Arimura T, etal., J Biol Chem. 2004 Feb 20;279(8):6746-52. Epub 2003 Dec 3.
Pubmed: (View Article at PubMed) PMID:14660611
DOI: Full-text: DOI:10.1074/jbc.M311849200

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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CRRD Object Information
CRRD ID: 1580827
Created: 2006-08-28
Species: All species
Last Modified: 2006-08-28
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.