Cardiac Troponin Mutations and Restrictive Cardiomyopathy

Abstract

Mutations in sarcomeric proteins have recently been established as heritable causes of Restrictive Cardiomyopathy (RCM). RCM is clinically characterized as a defect in cardiac diastolic function, such as, impaired ventricular relaxation, reduced diastolic volume and increased end-diastolic pressure. To date, mutations have been identified in the cardiac genes for desmin, α-actin, troponin I and troponin T. Functional studies in skinned muscle fibers reconstituted with troponin mutants have established phenotypes consistent with the clinical findings which include an increase in myofilament Ca2+ sensitivity and basal force. Moreover, when RCM mutants are incorporated into reconstituted myofilaments, the ability to inhibit the ATPase activity is reduced. A majority of the mutations cluster in specific regions of cardiac troponin and appear to be mutational “hot spots”. This paper highlights the functional and clinical characteristics of RCM linked mutations within the troponin complex.

Animal Models of Heart Failure

“…However, for inherited restrictive cardiomyopathies, several recent studies demonstrate that specific sarcomeric protein mutations are associated with defects in myocardial function and increased myofilament calcium sensitivity. 162 Mutations involving cardiac troponin I (cTnI), [163][164][165][166][167] cardiac troponin T, [165][166][167][168][169] desmin, 170 -174 and ␣-␤-crystallin 175 have been most often associated with a restrictive cardiomyopathy phenotype, although alternative mutations of these proteins can also produce a hypertrophic cardiomyopathy phenotype. 166,176,177 The histological abnormalities observed in restrictive cardiomyopathies vary with, and are often diagnostic of, the underlying etiology.…”

“…However, some familial restrictive cardiomyopathies are not apparent until adulthood. 162 Atrial fibrillation is seen with many etiologies of restrictive cardiomyopathy. Ventricular arrhythmias are particularly prevalent among patients with sarcoidosis and some of the mutations associated with familial restrictive cardiomyopathy.…”

Genetics and Disease of Ventricular Muscle

“…RCM can occur as a primary cardiomyopathy with a genetic etiology or occur secondary to infiltrative or systemic disorders such as amyloidosis and sarcoidosis. Mutations in seven sarcomere protein genes (Table 1), as well as in DES, encoding the cytoskeletal protein desmin, have been found in sporadic cases and families with RCM (Parvatiyar et al 2010a;SenChowdry et al 2010;Caleshu et al 2011). The differential diagnosis of RCM includes HCM, which can also manifest with restrictive diastolic filling defects and atrial dilatation.…”

Sarcomere neutralization in inherited cardiomyopathy: small-molecule proof-of-concept to correct hyper-Ca2+-sensitive myofilaments

“…Mutations in myosin heavy chain, myosin-binding protein C, tropomyosin, cardiac troponin T, cardiac troponin I (cTnI), actin, and cardiac troponin C (cTnC) have all been implicated as disease causing. Like HCM, restrictive cardiomyopathy (RCM) is a genetic disorder of the sarcomere with many of the same genes being causative and even the same mutations resulting in HCM in one patient and RCM in another (24,34). RCM mutations lead to a more severe disease characterized by diastolic dysfunction and heart failure.…”