Loss of mXinalpha, an intercalated disk protein, results in cardiac hypertrophy and cardiomyopathy with conduction defects.
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, mXinalpha and mXinbeta. The human homolog of mXinalpha, Cmya1, maps to chromosomal region 3p21.2-21.3, near a dilated cardiomyopathy with conduction defect-2 locus. Here we report that mXinalpha-null mouse hearts are hypertrophied and exhibit fibrosis, indicative of cardiomyopathy. A significant upregulation of mXinbeta likely provides partial compensation and accounts for the viability of the mXinalpha-null mice. Ultrastructural studies of mXinalpha-null mouse hearts reveal intercalated disk disruption and myofilament disarray. In mXinalpha-null mice, there is a significant decrease in the expression level of p120-catenin, beta-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 mXinalpha-null mouse heart, which, together with previously observed abnormal electrophysiological properties of mXinalpha-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 mXinalpha-deficient hearts. Thus mXinalpha 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 mXinalpha-knockout mouse line provides a novel model of cardiac hypertrophy and cardiomyopathy with conduction defects.
Gustafson-Wagner
Elisabeth A
EA
Department of Biological Sciences, University of Iowa, Iowa City, IA 52242, USA.
Sinn
Haley W
HW
Chen
Yen-Lin
YL
Wang
Da-Zhi
DZ
Reiter
Rebecca S
RS
Lin
Jenny L-C
JL
Yang
Baoli
B
Williamson
Roger A
RA
Chen
Ju
J
Lin
Cheng-I
CI
Lin
Jim J-C
JJ
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000473:pathology / Q000503:physiopathology*; D006332:Cardiomegaly / Q000473:pathology / Q000503:physiopathology*; D009202:Cardiomyopathies / Q000473:pathology / Q000503:physiopathology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006329:Heart Conduction System / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000378:metabolism*; D012508:Sarcolemma / Q000378:metabolism* / Q000473:pathology
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C118478:Xin protein, mouse