title: Molecular insights from a novel cardiac troponin I mouse model of familial hypertrophic cardiomyopathy.
abstract: 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.
authors.affiliation: Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Locked Bag 6, Newtown NSW 2042 Australia.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Tsoutsman
authors.forename: Jessica
authors.initials: J
authors.lastname: Chung
authors.forename: Alessandra
authors.initials: A
authors.lastname: Doolan
authors.forename: Lan
authors.initials: L
authors.lastname: Nguyen
authors.forename: Iwan A
authors.initials: IA
authors.lastname: Williams
authors.forename: Emily
authors.initials: E
authors.lastname: Tu
authors.forename: Lien
authors.initials: L
authors.lastname: Lam
authors.forename: Charles G
authors.initials: CG
authors.lastname: Bailey
authors.forename: John E J
authors.initials: JE
authors.lastname: Rasko
authors.forename: David G
authors.initials: DG
authors.lastname: Allen
authors.forename: Christopher
authors.initials: C
authors.lastname: Semsarian
mesh_terms: 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
chemical_list: D012333:RNA, Messenger; D019210:Troponin I