Hypertrophic cardiomyopathy: from gene defect to clinical disease

Abstract

Major advances have been made over the last decade in our understanding of the molecular basis of several cardiac conditions. Hypertrophic cardiomyopathy (HCM) was the first cardiac disorder in which a genetic basis was identified and as such, has acted as a paradigm for the study of an inherited cardiac disorder. HCM can result in clinical symptoms ranging from no symptoms to severe heart failure and premature sudden death. HCM is the commonest cause of sudden death in those aged less than 35 years, including competitive athletes. At least ten genes have now been identified, defects in which cause HCM. All of these genes encode proteins which comprise the basic contractile unit of the heart, i.e. the sarcomere. While much is now known about which genes cause disease and the various clinical presentations, very little is known about how these gene defects cause disease, and what factors modify the expression of the mutant genes. Studies in both cell culture and animal models of HCM are now beginning to shed light on the signalling pathways involved in HCM, and the role of both environmental and genetic modifying factors. Understanding these mechanisms will ultimately improve our knowledge of the basic biology of heart muscle function, and will therefore provide new avenues for treating cardiovascular disease in man.

Myosin binding protein C: Structural abnormalities in familial hypertrophic cardiomyopathy

“…http://www.cell-research.com caused by the expression of abnormal contractile proteins in the heart muscle. To date, mutations in ten sarcomeric proteins have been identified as causes of FHC [20]. The mechanism by which MyBPC mutations cause sarcomeric dysfunction at present poorly understood, but has provided a substantial stimulus to efforts to understand the basic biochemistry and physiology of this important molecule.…”

“…FHC is a clinically and genetically heterogeneous disorder characterised macroscopically by increased left ventricular mass in the absence of any apparent loading stress, and histologically by myofibrillar and myocyte disarray and fibrosis [20]. Clinically, the extent of hypertrophy determines Multiple alignments of MyBPC isoforms from different species.…”

A novel mouse model of X-linked cardiac hypertrophy

“…These exhibit similar echo presentations, but have different histological characteristics and may show ventricular preexcitation (1). Transgenic and knockout mouse models with mutations in genes encoding sarcomeric proteins have demonstrated parallels with human clinical disease (7,12,20). In addition, mouse models for human cardiomyopathies involving fatty acid oxidation or carnitine metabolic disorders also have been generated (11,15,26,41).…”

Severe Heart Failure and Early Mortality in a Double-Mutation Mouse Model of Familial Hypertrophic Cardiomyopathy

“…These causative genes most commonly encode proteins that are components of the sarcomere, eg, ␤-myosin heavy chain (␤-MHC) and myosin-binding protein C (MyBP-C). 1,6 The long-standing paradigm has been that a single mutation in a single gene leads to FHC, hence the reference to FHC as a "monogenic" disorder.…”