title: Transgenic modeling of a cardiac troponin I mutation linked to familial hypertrophic cardiomyopathy.
abstract: Multiple mutations in cardiac troponin I (cTnI) have been associated with familial hypertrophic cardiomyopathy. Two mutations are located in the cTnI inhibitory domain, a highly negatively charged region that alternately binds to either actin or troponin C, depending on the intracellular concentration of calcium. This region is critical to the inhibition of actin-myosin crossbridge formation when intracellular calcium is low. We modeled one of the inhibitory domain mutations, arginine145-->glycine (TnI(146Gly) in the mouse sequence), by cardiac-specific expression of the mutated protein in transgenic mice. Multiple lines were generated with varying degrees of expression to establish a dose relationship; the severity of phenotype could be correlated directly with transgene expression levels. Transgenic mice overexpressing wild-type cTnI were generated as controls and analyzed in parallel with the TnI(146Gly) animals. The control mice showed no abnormalities, indicating that the phenotype of TnI(146Gly) was not simply an artifact of transgenesis. In contrast, TnI(146Gly) mice showed cardiomyocyte disarray and interstitial fibrosis and suffered premature death. The functional alterations that seem to be responsible for the development of cardiac disease include increased skinned fiber sensitivity to calcium and, at the whole organ level, hypercontractility with diastolic dysfunction. Severely affected lines develop a pathology similar to human familial hypertrophic cardiomyopathy but within a dramatically shortened time frame. These data establish the causality of this mutation for cardiac disease, provide an animal model for understanding the resultant pathogenic structure-function relationships, and highlight the differences in phenotype severity of the troponin mutations between human and mouse hearts.
authors.affiliation: Department of Pediatrics, Division of Molecular Cardiovascular Biology, The Children's Hospital Research Foundation, Cincinnati, Ohio, USA.
authors.forename: J
authors.initials: J
authors.lastname: James
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: H
authors.initials: H
authors.lastname: Osinska
authors.forename: A
authors.initials: A
authors.lastname: Sanbe
authors.forename: R
authors.initials: R
authors.lastname: Klevitsky
authors.forename: T E
authors.initials: TE
authors.lastname: Hewett
authors.forename: J
authors.initials: J
authors.lastname: Robbins
mesh_terms: D000199:Actins / Q000737:chemistry; D000367:Age Factors; D019943:Amino Acid Substitution; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D005260:Female; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D009154:Mutation; D009206:Myocardium / Q000378:metabolism*; D009218:Myosins / Q000737:chemistry; D010641:Phenotype; D020033:Protein Isoforms / Q000096:biosynthesis; D012313:RNA / Q000096:biosynthesis; D013329:Structure-Activity Relationship; D016019:Survival Analysis; D019210:Troponin I / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*
chemical_list: D000199:Actins; D020033:Protein Isoforms; D019210:Troponin I; D012313:RNA; D009218:Myosins; D002118:Calcium