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| Subject Categories: RNA | Molecular Biology of Disease |
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| The EMBO Journal
(2004) 23, 885–896, doi:10.1038/sj.emboj.7600054 Published online 12 February 2004 |
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| Dilated cardiomyopathy caused by tissue-specific ablation of SC35 in the heart |
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| Jian-Hua Ding1, Xiangdong Xu1, Dongmei Yang2, Pao-Hsien Chu3, 4, Nancy D Dalton3, Zhen Ye1, Joanne M Yeakley1, 5, Heping Cheng2, Rui-Ping Xiao2, John Ross Jr3, Ju Chen3 and Xiang-Dong Fu1 |
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1 Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA, USA 2 Laboratory of Cardiovascular Science, Gerontology Research Center, NIA, NIH, Baltimore, MD, USA 3 Department of Medicine and Institute of Molecular Medicine, University of California at San Diego, La Jolla, CA, USA To whom correspondence should be addressed Xiang-Dong Fu, Department of Cellular and Molecular Medicine, University of California at San Diego, CMM(W) 231A, 9500 Gilman Drive, La Jolla, CA 92093-0651, USA. Tel.: +1 858 534 4937; Fax: +1 858 534 8549; E-mail: xdfu@ucsd.edu 4 Present address: The First Cardiovascular Department, Internal Medicine, Chang Gung Memorial Hospital, Taipei, Taiwan 5 Current address: Illumina, Inc., 9885 Towne Centre Drive, San Diego, CA 92121-1975, USA Received 23 September 2003; Accepted 5 December 2003; Published online 12 February 2004. |
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| Abstract |
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| 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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| Keywords: heart disease, splicing regulation, SR proteins |
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Top of page MORE ARTICLES LIKE THISThese links to content published by NPG are automatically generated RESEARCHJournal of Investigative Dermatology Original Article Nature Medicine Article (01 Nov 2001) Deficiency of PDK1 in cardiac muscle results in heart failure and increased sensitivity to hypoxia The EMBO Journal Article (15 Sep 2003) |
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