Referenced in: none

Automatically associated channels: Kir6.2

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

Authors: Jian-Hua Ding, Xiangdong Xu, Dongmei Yang, Pao-Hsien Chu, Nancy D Dalton, Zhen Ye, Joanne M Yeakley, Heping Cheng, Rui-Ping Xiao, John Ross, Ju Chen, Xiang-Dong Fu

Journal, date & volume: EMBO J., 2004 Feb 25 , 23, 885-96

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/14963485

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.