Identifying Sarcomere Gene Mutations in Hypertrophic Cardiomyopathy

Abstract

This article provides an historical and personal perspective on the discovery of genetic causes for hypertrophic cardiomyopathy (HCM). Extraordinary insights of physicians who initially detailed remarkable and varied manifestations of the disorder, collaboration among multidisciplinary teams with skills in clinical diagnostics and molecular genetics, and hard work by scores of trainees, solved the etiologic riddle of HCM, and unexpectedly demonstrated mutations in sarcomere protein genes as the cause of disease. In addition to celebrating 20 years of genetic research in HCM, this article serves as an introductory overview to a thematic review series that will present contemporary advances in the field of hypertrophic heart disease. Through the continued application of advances in genetic methodologies, combined with biochemical and biophysical analyses of the consequences of human mutations, fundamental knowledge about HCM and sarcomere biology has emerged. Expanding research to elucidate the mechanisms by which subtle genetic variation in contractile proteins remodel the human heart remains an exciting opportunity, one with considerable promise to provide new strategies to limit or even prevent HCM pathogenesis.

Two Hundred Eight Patients With Apical Hypertrophic Cardiomyopathy in China: Clinical Feature, Prognosis, and Comparison of Pure and Mixed Forms

“…Some studies show that gene mutations, such as the troponin T, β-myosin heavy chain, and α-cardiac actin are associated with AHCM 29 -31 ; however, the proportion of genotype positive is lower in patients with AHCM than common HCM. 32 Genome-wide association studies and gene expression profiling are needed for a better understanding of the genetic background of the disease. Another potential limitation was the loss of follow-up.…”

Atomic model of the human cardiac muscle myosin filament

“…We have applied single-particle analysis to myosin filaments from a variety of muscle types including vertebrate skeletal and cardiac muscles (13,14) and invertebrate striated muscle (15). A similar approach has been used by others in the analysis of mouse cardiac myosin filament structure (16), where myosin heads were also found to adopt a paired conformation similar to that in tarantula myosin filaments.Mutations in human cardiac muscle myosin and its associated proteins, cMyBP-C and titin, are known to cause a number of human cardiomyopathies including familial hypertrophic cardiomyopathy and dilated cardiomyopathy (17,18). A detailed knowledge of the structure of human cardiac myosin filaments in the normal (undiseased) relaxed state is likely to be important in understanding how the mutations give rise to these cardiomyopathies.…”

“…Mutations in human cardiac muscle myosin and its associated proteins, cMyBP-C and titin, are known to cause a number of human cardiomyopathies including familial hypertrophic cardiomyopathy and dilated cardiomyopathy (17,18). A detailed knowledge of the structure of human cardiac myosin filaments in the normal (undiseased) relaxed state is likely to be important in understanding how the mutations give rise to these cardiomyopathies.…”

Troponin I Mutations R146G and R21C Alter Cardiac Troponin Function, Contractile Properties, and Modulation by Protein Kinase A (PKA)-mediated Phosphorylation

“…Familial hypertrophic cardiomyopathy (HCM) 2 has been identified as a major autosomal dominant disease and is highly correlated with mutations detected in myofilament contractile proteins (1). Although the majority of mutations are found in myosin and cardiac myosin-binding protein C (cMyBP-C), mutations have also been identified in thin filament regulatory proteins such as cardiac troponin I (cTnI), which is a subunit of the cardiac troponin (cTn) complex that has a critical role in the activation and relaxation of cardiac muscle (2).…”