© 2000 American Heart Association, Inc.
Integrative Physiology |
Transgenic Modeling of a Cardiac Troponin I Mutation Linked to Familial Hypertrophic Cardiomyopathy
From the Department of Pediatrics, Division of Molecular Cardiovascular Biology, The Children’s Hospital Research Foundation, Cincinnati, Ohio.
Correspondence to J. Robbins, PhD, Division of Molecular Cardiovascular Biology, 3333 Burnet Ave, Cincinnati, OH 45229-3039. E-mail jeff.robbins{at}chmcc.org
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 (TnI146Gly 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
TnI146Gly animals. The control mice showed
no abnormalities, indicating that the phenotype of
TnI146Gly was not simply an artifact of
transgenesis. In contrast, TnI146Gly 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.
Key Words: hypertrophic cardiomyopathy mouse cardiac troponin I sarcomere
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