Molecular insights from a novel cardiac troponin I mouse model of familial hypertrophic cardiomyopathy.
Gene mutations in cardiac troponin I (cTnI) account for up to 5% of genotyped families with familial hypertrophic cardiomyopathy (FHC). Little is known about how cTnI mutations cause disease. Five lines of transgenic mice were generated which overexpress the human disease-causing cTnI gene mutation, Gly203Ser (designated cTnI-G203S), in a cardiac-specific manner. Mice were compared to transgenic mice that overexpress normal cTnI (cTnI-wt) and non-transgenic littermates (NTG). cTnI-G203S mice developed all the characteristic features of FHC by age 21 weeks. Left ventricular hypertrophy was observed on echocardiography (1.25+/-0.05 mm vs. 0.86+/-0.02 mm in cTnI-wt, P<0.01), associated with a significant 4-fold increase in RNA markers of hypertrophy, ANF and BNP. Myocyte hypertrophy, myofiber disarray and interstitial fibrosis were observed in cTnI-G203S mice. Expression of the cTnI-G203S mutation in neonatal cardiomyocytes resulted in a significant increase in myocyte volume, and reduced interactions with both troponins T and C. Ca2+ cycling was abnormal in adult cardiomyocytes extracted from cTnI-G203S mice, with a prolonged decay constant in Ca2+ transients and a reduced decay constant in response to caffeine treatment. Mice with the cTnI-G203S gene mutation develop all the phenotypic features of human FHC. The cTnI-G203S mutation disrupts interactions with partner proteins, and results in intracellular Ca2+ dysregulation early in life, suggesting a pathogenic role in development of FHC.
Tsoutsman
Tatiana
T
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Locked Bag 6, Newtown NSW 2042 Australia.
Chung
Jessica
J
Doolan
Alessandra
A
Nguyen
Lan
L
Williams
Iwan A
IA
Tu
Emily
E
Lam
Lien
L
Bailey
Charles G
CG
Rasko
John E J
JE
Allen
David G
DG
Semsarian
Christopher
C
D000818:Animals; D000831:Animals, Newborn; D020013:Calcium Signaling; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D048429:Cell Size; D004195:Disease Models, Animal; D004562:Electrocardiography; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D009154:Mutation; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000648:ultrastructure; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism*; D019210:Troponin I / Q000235:genetics* / Q000502:physiology
D012333:RNA, Messenger; D019210:Troponin I