Dilated cardiomyopathy caused by tissue-specific ablation of SC35 in the heart |
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Authors: | Ding Jian-Hua Xu Xiangdong Yang Dongmei Chu Pao-Hsien Dalton Nancy D Ye Zhen Yeakley Joanne M Cheng Heping Xiao Rui-Ping Ross John Chen Ju Fu Xiang-Dong |
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Affiliation: | Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093-0651, USA. |
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Abstract: | Many genetic diseases are caused by mutations in cis-acting splicing signals, but few are triggered by defective trans-acting splicing factors. Here we report that tissue-specific ablation of the splicing factor SC35 in the heart causes dilated cardiomyopathy (DCM). Although SC35 was deleted early in cardiogenesis by using the MLC-2v-Cre transgenic mouse, heart development appeared largely unaffected, with the DCM phenotype developing 3-5 weeks after birth and the mutant animals having a normal life span. This nonlethal phenotype allowed the identification of downregulated genes by microarray, one of which was the cardiac-specific ryanodine receptor 2. We showed that downregulation of this critical Ca2+ release channel preceded disease symptoms and that the mutant cardiomyocytes exhibited frequency-dependent excitation-contraction coupling defects. The implication of SC35 in heart disease agrees with a recently documented link of SC35 expression to heart failure and interference of splicing regulation during infection by myocarditis-causing viruses. These studies raise a new paradigm for the etiology of certain human heart diseases of genetic or environmental origin that may be triggered by dysfunction in RNA processing. |
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