Abstract 393: Targeted Deletion of mXinα Gene, Encoding an Intercalated Disc Protein, Leads to Cardiac hypertrophy
Originally isolated in the chick, with subsequent identification of the mouse homologues (mXinα and mXinβ), Xin was hypothesized to play a role in heart development and function. The human homologue (named Cardiomyopathy-associated 1, Cmya1, gene) of mXinα was mapped to 3p21.2–p21.3 near the loci for a dilated cardiomyopathy with conduction defect-2 and arrhythmogenic right ventricular dysplasia-5. Predicted Xin proteins all contain a region with 15~28 16-aa repeating units (Xin repeats), and a proline-rich region. The Xin repeats interact with actin filaments. Colocalization of mXinα protein with N-cadherin and β-catenin to the intercalated disc is observed throughout mouse embryogenesis and into adulthood. Yeast two-hybrid analysis reveals that β-catenin directly interacts with mXinα at a binding domain comprised by amino acids 533–746 of mXinα, overlapping with the last 4 Xin repeats. The mXinα-null mice were viable and fertile. The viability likely results from functional compensation through an upregulation of mXinβ. The mXinα-deficient hearts exhibited an increase in heart weight/body weight ratio and in myofiber width when compared to the wild type control. Ultrastructural studies of hearts from mXinα-null mice revealed a significant disruption of the intercalated disc ultrastructure and disarray of myofilaments. Additionally, several areas dispersed throughout the mXinα-deficient heart sections stained positive for collagen by Masson’s trichrome stain, indicative of fibrosis. The amount of fibrosis detected in the mXinα-deficient mice increases with age. Thus, mXinα-deficient mice are predisposed to hypertrophic cardiomyopathy. The hypertrophy begins with intercalated disc disruption, myofibril disarray and increased interstitial fibrosis as early as 3– 4 months of age and is ultimately observed in increased myofiber width and in the enlarged heart. These results suggest that mXinα is involved in regulation of the hypertrophy response and maintenance of the structural integrity of the intercalated disc in normal mice, likely through the association of mXinα with β-catenin and actin filaments in the adherens junction complex.