Identifying sarcomere gene mutations in hypertrophic cardiomyopathy: a personal history

Abstract

This review provides an historical and personal perspective on the discovery of genetic causes for hypertrophic cardiomyopathy (HCM). Extraordinary insights by 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.

Figure 1

The anatomic and histopathologic findings of HCM. A. Gross anatomy of an HCM heart shows marked hypertrophy with involvement of the interventricular septum, left ventricular free wall, and papillary muscle. Wall thickness (bar) = 20 mm (normal ≤ 12 mm). Left atrial enlargement is also evident. B. Mason trichrome stained ventricular tissue reveals markedly disorganized, enlarged myocytes (magenta) with prominent nuclei. The interstitium (blue) in expanded in HCM due to increased numbers of fibroblasts and extracellular matrix material.

Figure 2

Definitive and posited HCM genes. A schematic representation of a sarcomere (the unit of contraction that spans two neighboring Z-bands) is shown with the locations of thin and thick filaments in relationship to I, A and H bands. The detailed representation of the A band, highlights definitive HCM genes (black) that encode β myosin heavy chain (MYH7), myosin binding protein C (MYPBC3), troponin T (TNNT2), α tropomyosin (TPMI), myosin regulatory light chain (MYL2), myosin essential light chain (MYL3) and (ACTC). More than 50% of human mutations occur in β myosin heavy chain and myosin binding protein C. Additional genes that have been implicated in HCM (brown) encode Z-disc proteins, troponin C (TNNT1), titin (TNT), α myosin heavy chain (MYH6, not depicted) and phospholamban (PLN, not depicted).