Molecular Etiology and Pathogenesis of Hereditary Cardiomyopathy

Abstract

Cardiomyopathy is defined as a cardiac disease caused by functional abnormality of cardiac muscle, and the etiology of the functional abnormality includes both extrinsic and intrinsic factors. Cardiomyopathy caused by the intrinsic factors is defined as idiopathic or primary cardiomyopathy, and there are several clinical phenotypes, including hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). The major intrinsic factor is gene mutations, and linkage studies, as well as candidate gene approaches, have deciphered multiple disease genes for hereditary primary cardiomyopathy. Of note is that mutations in the same disease gene can be found in different clinical phenotypes of cardiomyopathy. Functional analyses of disease-related mutations have revealed that characteristic functional alterations are associated with the clinical phenotypes, such that increased and decreased Ca 2+ sensitivity because of sarcomere mutations are associated with HCM and DCM, respectively. In addition, recent data have suggested that mutations in the Z-disc components found in HCM and DCM may result in increased and decreased stiffness of the sarcomere (ie, stiff sarcomere and loose sarcomere, respectively). More recently, mutations in the components of the I region can be found in hereditary cardiomyopathy, further complicating the etiology of primary cardiomyopathy. (Circ J 2008; Suppl A: A-38 -A-48)

Usefulness of Serum Cardiac Troponins T and I to Predict Cardiac Molecular Changes and Cardiac Damage in Patients With Hypertrophic Cardiomyopathy

“…11,23) The mutation includes four genes encoding proteins of cardiac sarcomeres that have been implicated in causing HCM: β-myosin heavy chain, cardiac troponin, α-tropomyosin, and myosin-binding protein C genes. 24,25) However, a genetic diagnosis was not performed in the present study. In addition, we did not determine the prognosis in these patients because of the small sample and the incidence of cardiac events in these HCM patients.…”

Molecular basis of hereditary cardiomyopathy: abnormalities in calcium sensitivity, stretch response, stress response and beyond

“…Clinical manifestations of HCM due to the sarcomere mutations were in general different from each other, but there were some tendencies of genotype-phenotype correlations. 11,12 For example, Watkins et al 13 hypothesized that the MYH7 mutations leading to amino acid changes with charge alteration was associated with poor survival prognosis. However, it is not simply applicable to all the MYH7 mutations.…”

“…68 In addition, another DCM-associated TTN mutation found in the Tcapbinding domain decreased the binding to Tcap. 68 As the Z-disc element mutations result in decreased binding among the elements, we hypothesize that DCM is the disease of 'loose sarcomere' 12,33 ( Figure 3). The loose sarcomere is evident in an animal model of DCM, CSRP3 (MLP) knock-out mouse, in which Z-disc was wide and stretch response was impaired.…”

Phospholamban C-terminal Residues Are Critical Determinants of the Structure and Function of the Calcium ATPase Regulatory Complex

“…Dilated cardiomyopathy and hypertrophic cardiomyopathy are the primary causes of heart failure (2,3) and are often associated with mutations in genes encoding cardiac calcium (Ca 2ϩ )-handling proteins including phospholamban (PLB) 5 (3)(4)(5)(6)(7)(8)(9)(10)(11)(12). PLB is a homopentameric, integral sarcoplasmic reticulum membrane protein that upon deoligomerization into active monomers reversibly inhibits sarco/ endoplasmic reticulum calcium ATPase (SERCA) (13)(14)(15), thereby directly regulating cardiac Ca 2ϩ kinetics and contractility (16 -21).…”