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ABSTRACT: Background
Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disease characterized by thickening of ventricular walls and decreased left ventricular chamber volume. The majority of HCM-associated mutations are found in genes encoding sarcomere proteins. Herein, we set out to functionally characterize a novel HCM-associated mutation (K206I-TNNI3) and elucidate the mechanism of dysfunction at the level of myofilament proteins.Methods and results
The male index case was diagnosed with HCM after an out-of-hospital cardiac arrest, which was followed by comprehensive clinical evaluation, transthoracic echocardiography, and clinical genetic testing. To determine molecular mechanism(s) of the mutant human cardiac troponin I (K206I), we tested the Ca(2+) dependence of thin filament-activated myosin-S1-ATPase activity in a reconstituted, regulated, actomyosin system comparing wild-type human troponin complex, 50% mix of K206I/wildtype, or 100% K206I. We also exchanged native troponin detergent extracted fibers with reconstituted troponin containing either wildtype or a 65% mix of K206I/wildtype and measured force generation. The Ca(2+) sensitivity of the myofilaments containing the K206I variant was significantly increased, and when treated with 20 µmol/L (-)-epigallocatechin gallate (green tea) was restored back to wild-type levels in ATPase and force measurements. The K206I mutation impairs the ability of the troponin I to inhibit ATPase activity in the absence of calcium-bound human cardiac troponin C. The ability of calcium-bound human cardiac troponin C to neutralize the inhibition of K206I was greater than with wild-type TnI.Conclusions
Compromised interactions of K206I with actin and hcTnC may lead to impaired relaxation and HCM.
SUBMITTER: Warren CM
PROVIDER: S-EPMC4681609 | biostudies-literature | 2015 Dec
REPOSITORIES: biostudies-literature
Warren Chad M CM Karam Chehade N CN Wolska Beata M BM Kobayashi Tomoyoshi T de Tombe Pieter P PP Arteaga Grace M GM Bos J Martijn JM Ackerman Michael J MJ Solaro R John RJ
Circulation. Cardiovascular genetics 20151109 6
<h4>Background</h4>Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disease characterized by thickening of ventricular walls and decreased left ventricular chamber volume. The majority of HCM-associated mutations are found in genes encoding sarcomere proteins. Herein, we set out to functionally characterize a novel HCM-associated mutation (K206I-TNNI3) and elucidate the mechanism of dysfunction at the level of myofilament proteins.<h4>Methods and results</h4>The male ...[more]