Genetic Clues to Disease Pathways in Hypertrophic and Dilated Cardiomyopathies
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Molecular genetic analysis of cardiomyopathies inherited as single-gene disorders is now a relatively mature field. Nevertheless, research in this area continues to throw up unexpected complexities that by challenging prevailing paradigms contribute important new insights into myocardial biology and disease processes.
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Hypertrophic Cardiomyopathy: More Than a Disease of the Sarcomere?
A common finding in genetic analyses of an inherited condition is that a single clinical entity can be caused by mutations in multiple genes. Similarly, different mutations within a single gene can give rise to surprisingly diverse clinical conditions. Against this background, the genetic complexity that has been shown to underlie hypertrophic cardiomyopathy (HCM) is not unusual. Initially, the emerging picture appeared clear; namely, that HCM was a disease of the sarcomere, attributable to subtle perturbations (mostly missense mutations) affecting a number of components of the cardiac contractile apparatus.1 As further candidate genes were tested, it became apparent that most, if not all, sarcomeric proteins could be mutated to cause HCM.2,3 Although still fitting a single paradigm, these disease-genes encode proteins that contribute to cardiac contractility in very diverse ways — some enzymatic, some structural and others regulatory. Perhaps not surprisingly then, functional analyses have not shown a unifying abnormality of contractility as an explanation of the pathway to the HCM phenotype.4 Although the majority of HCM mutant contractile proteins lead to enhanced contractility, others seem to have the opposite effect by reducing maximum force output.5–7 A proposal has been made that instead, the common abnormality is increased energy cost of force production,4,5,8 and this has been supported by observations of energetic compromise in a mouse model9 and by data on ATP consumption in mutant sarcomeres.10 Testing of positional candidate genes involved in ATP homeostasis has recently lead to identification of AMP-activated protein kinase (AMPK) as a disease-gene for …