TY - JOUR
T1 - A familial hypertrophic cardiomyopathy α-tropomyosin mutation causes severe cardiac hypertrophy and death in mice
AU - Prabhakar, Rethinasamy
AU - Boivin, Greg P.
AU - Grupp, Ingrid L.
AU - Hoit, Brian
AU - Arteaga, Grace
AU - Solaro, R. John
AU - Wieczorek, David F.
N1 - Funding Information:
We thank Gilbert Newmann, Jim Donavan and Julia Sillis for their technical assistance. This work was funded by grants (HL54912 and HL22619) from the NIH NHLBI to DFW. GMA was supported by a Minority Individual in Postdoctoral Training Supplement to R37 HL 22231 (RJS).
PY - 2001
Y1 - 2001
N2 - Tropomyosin, an essential component of the sarcomere, regulates muscle contraction through Ca2+-mediated activation. Familial hypertrophic cardiomyopathy (FHC) is caused by mutations in numerous cardiac sarcomeric proteins, including myosin heavy and light chains, actin, troponin T and I, myosin binding protein C, and α-tropomyosin. This study developed transgenic mouse lines that encode an FHC mutation in α-tropomyosin: this mutation is an amino acid substitution at codon 180 (Glu180Gly) which occurs in a troponin T binding region. Non-transgenic and control mice expressing wildtype α-tropomyosin demonstrate no morphological or physiological changes. Expression of exogenous mutant tropomyosin leads to a concomitant decrease in endogenous α-tropomyosin without altering the expression of other contractile proteins. Histological analysis shows that initial pathological changes, which include ventricular concentric hypertrophy, fibrosis and atrial enlargement, are detected within 1 month. The disease-associated changes progressively increase and result in death between 4 and 5 months. Physiological analyses of the FHC mice using echocardiography, work-performing heart analyses, and force measurements of cardiac myofibers, demonstrate dramatic functional differences in diastolic performance and increased sensitivity to calcium. This report demonstrates that mutations in α-tropomyosin can be severely disruptive of sarcomeric function, which consequently triggers a dramatic hypertrophic response that culminates in lethality.
AB - Tropomyosin, an essential component of the sarcomere, regulates muscle contraction through Ca2+-mediated activation. Familial hypertrophic cardiomyopathy (FHC) is caused by mutations in numerous cardiac sarcomeric proteins, including myosin heavy and light chains, actin, troponin T and I, myosin binding protein C, and α-tropomyosin. This study developed transgenic mouse lines that encode an FHC mutation in α-tropomyosin: this mutation is an amino acid substitution at codon 180 (Glu180Gly) which occurs in a troponin T binding region. Non-transgenic and control mice expressing wildtype α-tropomyosin demonstrate no morphological or physiological changes. Expression of exogenous mutant tropomyosin leads to a concomitant decrease in endogenous α-tropomyosin without altering the expression of other contractile proteins. Histological analysis shows that initial pathological changes, which include ventricular concentric hypertrophy, fibrosis and atrial enlargement, are detected within 1 month. The disease-associated changes progressively increase and result in death between 4 and 5 months. Physiological analyses of the FHC mice using echocardiography, work-performing heart analyses, and force measurements of cardiac myofibers, demonstrate dramatic functional differences in diastolic performance and increased sensitivity to calcium. This report demonstrates that mutations in α-tropomyosin can be severely disruptive of sarcomeric function, which consequently triggers a dramatic hypertrophic response that culminates in lethality.
KW - Cardiac hypertrophy
KW - Familial hypertrophic cardiomyopathy
KW - Sarcomeric function
KW - Transgenic mice
KW - Tropomyosin
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U2 - 10.1006/jmcc.2001.1445
DO - 10.1006/jmcc.2001.1445
M3 - Article
C2 - 11603924
AN - SCOPUS:0034781383
SN - 0022-2828
VL - 33
SP - 1815
EP - 1828
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
IS - 10
ER -