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Loss of mXin, an intercalated disk protein, results in cardiac hypertrophy and cardiomyopathy with conduction defects

Departments of ¹Biological Sciences and ⁴Obstetrics and Gynecology, University of Iowa, Iowa City, Iowa; ²Institutes of Physiology, Pharmacology, and Life Sciences, National Defense Medical Center, Taipei, Taiwan, Republic of China; ³Department of Cell and Developmental Biology, Carolina Cardiovascular Biology Center, University of North Carolina, Chapel Hill, North Carolina; and ⁵Department of Medicine, University of California-San Diego, La Jolla, California

Submitted 11 July 2007 ; accepted in final form 27 August 2007

The intercalated disk protein Xin was originally discovered in chicken striated muscle and implicated in cardiac morphogenesis. In the mouse, there are two homologous genes, mXin and mXin. The human homolog of mXin, Cmya1, maps to chromosomal region 3p21.2–21.3, near a dilated cardiomyopathy with conduction defect-2 locus. Here we report that mXin-null mouse hearts are hypertrophied and exhibit fibrosis, indicative of cardiomyopathy. A significant upregulation of mXin likely provides partial compensation and accounts for the viability of the mXin-null mice. Ultrastructural studies of mXin-null mouse hearts reveal intercalated disk disruption and myofilament disarray. In mXin-null mice, there is a significant decrease in the expression level of p120-catenin, -catenin, N-cadherin, and desmoplakin, which could compromise the integrity of the intercalated disks and functionally weaken adhesion, leading to cardiac defects. Additionally, altered localization and decreased expression of connexin 43 are observed in the mXin-null mouse heart, which, together with previously observed abnormal electrophysiological properties of mXin-deficient mouse ventricular myocytes, could potentially lead to conduction defects. Indeed, ECG recordings on isolated, perfused hearts (Langendorff preparations) show a significantly prolonged QT interval in mXin-deficient hearts. Thus mXin functions in regulating the hypertrophic response and maintaining the structural integrity of the intercalated disk in normal mice, likely through its association with adherens junctional components and actin cytoskeleton. The mXin-knockout mouse line provides a novel model of cardiac hypertrophy and cardiomyopathy with conduction defects.

Xin repeat proteins; N-cadherin; -catenin; p120-catenin; connexin 43

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