Sarcomeric Proteins and Familial Hypertrophic Cardiomyopathy: Linking Mutations in Structural Proteins to Complex Cardiovascular Phenotypes

Abstract

Hypertrophic Cardiomyopathy (HCM) is a relatively common primary cardiac disorder defined as the presence of a hypertrophied left ventricle in the absence of any other diagnosed etiology. HCM is the most common cause of sudden cardiac death in young people which often occurs without precedent symptoms. The overall clinical phenotype of patients with HCM is broad, ranging from a complete lack of cardiovascular symptoms to exertional dyspnea, chest pain, and sudden death, often due to arrhythmias. To date, 270 independent mutations in nine sarcomeric protein genes have been linked to Familial Hypertrophic Cardiomyopathy (FHC), thus the clinical variability is matched by significant genetic heterogeneity. While the final clinical phenotype in patients with FHC is a result of multiple factors including modifier genes, environmental influences and genotype, initial screening studies had suggested that individual gene mutations could be linked to specific prognoses. Given that the sarcomeric genes linked to FHC encode proteins with known functions, a vast array of biochemical, biophysical and physiologic experimental approaches have been applied to elucidate the molecular mechanisms that underlie the pathogenesis of this complex cardiovascular disorder. In this review, to illustrate the basic relationship between protein dysfunction and disease pathogenesis we focus on representative gene mutations from each of the major structural components of the cardiac sarcomere: the thick filament (beta MyHC), the thin filament (cTnT and Tm) and associated proteins (MyBP-C). The results of these studies will lead to a better understanding of FHC and eventually identify targets for therapeutic intervention.

Myosin Transducer Mutations Differentially Affect Motor Function, Myofibril Structure, and the Performance of Skeletal and Cardiac Muscles

“…The N-terminal globular motor domain is a product inhibited ATPase comprised of several communicating domains and functional units (reviewed by Holmes, 1999, 2005;. Alterations to the various domains dramatically affect the biochemical and mechanical properties of the motor in vitro, and mutations that diminish or enhance the molecular performance of myosin in vivo are associated with the pathogenesis of both skeletal and cardiac myopathies (reviewed by Sellers, 1999;Redowicz, 2002;Oldfors et al, 2004;Chang and Potter, 2005;Laing and Nowak, 2005;Tardiff, 2005;Oldfors, 2007). Central to an understanding of myosinbased myopathies is a fundamental appreciation for how depressed or enhanced molecular motor function differentially affects diverse striated muscles.…”

“…Therefore, Drosophila is a valuable model system to explore dysfunction of multiple muscles resulting from enhanced or depressed motor activity. This is particularly beneficial because similar alterations in myosin performance are associated with the development and age-related progression of numerous skeletal and cardiac myopathies found in higher organisms (Sellers, 1999;Redowicz, 2002;Oldfors et al, 2004;Chang and Potter, 2005;Laing and Nowak, 2005;Tardiff, 2005;Oldfors, 2007).The Mhc 5 mutation maps close to the junction between the HF helix and hypervariable loop 1, a critical element of the transducer. Biochemical and structural studies of wild-type and engineered myosins have shown loop 1 to be involved in kinetic tuning of the motor by influencing a wide range of myosin activities (Kurzawa-Goertz et al, 1998;Sweeney et al, 1998;Clark et al, 2005).…”

Hypertrophic Cardiomyopathy: Genetic Alterations, Pathogenesis and Pathophysiology

“…Экспериментальные модели ГКМП выявляют изменение содержания внутриклеточного Са 2+ , включая снижение его уровня в саркоплазмати-ческом ретикулуме и увеличение концентрации кати-онов в диастолу [23,28] В последние годы накоплено множество научных доказательств, подтверждающих, что мутации белков саркомеров, в частности тонких филаментов (напри-мер, мутации кардиального тропонина Т), в действи-тельности повышают чувствительность контрактиль-ных элементов к Са 2+ и усиливают силу сокращения [29,30]. Биофизический анализ мутированных бел-ков саркомера, являющихся "гиперконтрактиль-ными", с завышенными энергетическими затратами для продукции силы сокращения, привел исследова-телей к более специфической гипотезе: молекулярная основа ГКМП представлена клеточным энергетиче-ским дефицитом, в результате неэкономной функции саркомеров [30,31].…”

Rescue of Familial Hypertrophic Cardiomyopathy by Altering Sarcomeric Exposure and Response to Calcium

“…Patients with FHC mutations in the α-tropomyosin (α-Tm) gene exhibit a wide phenotypic range of symptoms. In the United States, a small percentage (<5%) of FHC patients have mutations in α-Tm with relatively benign symptoms (19). In Japan, the incidence of FHC patients with mutations in α-Tm is still relatively low, but the symptoms are more pathological (20,21).…”