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Article

  • The EMBO Journal (2004) 23, 885 - 896
  • doi:10.1038/sj.emboj.7600054

Published online: 12 February 2004

Dilated cardiomyopathy caused by tissue-specific ablation of SC35 in the heart

Jian-Hua Ding1, Xiangdong Xu1, Dongmei Yang2, Pao-Hsien Chu3,a, Nancy D Dalton3, Zhen Ye1, Joanne M Yeakley1,b, Heping Cheng2, Rui-Ping Xiao2, John Ross Jr3, Ju Chen3 and Xiang-Dong Fu1

  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

Correspondence to:

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

aPresent address: The First Cardiovascular Department, Internal Medicine, Chang Gung Memorial Hospital, Taipei, Taiwan

bCurrent address: Illumina, Inc., 9885 Towne Centre Drive, San Diego, CA 92121-1975, USA

Received 23 September 2003; Accepted 5 December 2003

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.

  • Keywords:

    • heart disease,
    • splicing regulation,
    • SR proteins