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Mutations in the tropomyosin gene may induce cardiac hypertrophy or dilatation
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Genetics of CVD received a great boost in the 1990s with the discovery by Harvard’s Christine Seidman, MD, of the first gene for hypertrophic cardiomyopathy. Subsequent to this discovery, multiple genes were identified with hundreds of mutations that were responsible for hypertrophic cardiomyopathy (HCM). It became evident that most of the genes inducing the phenotype of HCM were occurring in the sarcomere proteins involved with contractility.
The other successful pursuit was the identification of genes responsible for dilated cardiomyopathy (DCM). The terms HCM and DCM have important implications as paradigms to understand cardiac growth and remodeling in response to injury, including the normal response to exercise. The heart compensates in response to normal exercise or injurious stimuli by hypertrophy in one of two modes.
In the case of exercise, and as in HCM, the heart generates sarcomeres in parallel, inducing thickened ventricular walls with normal or only slightly altered ventricular chamber size. The other response is dilation of the chamber while adding sarcomeres in series such that the ventricular wall thickness is usually normal. In general, the latter response tends to be associated deleterious effects with subsequent HF and, ultimately, death.
It is of interest that the initial response to disease such as MI or hypertension is hypertrophy with sarcomeres added in parallel. However, this compensated state, which tends to maintain normal or adequate function for a long time, may deteriorate into cardiac dilation and, presumably, sarcomeres added in series. The molecular mechanism for this transition from growth of sarcomeres in parallel to that of in series is unknown, as is the molecular mechanism that triggers one or either of these growth responses.
Several years ago, we showed that mutations occurring in different parts of the troponin T gene could induce either growth in parallel or in series, depending on which region of the gene was mutated. It remains of interest (and is somewhat fascinating) that mutations occurring in different regions of the same sarcomeric gene can provide either of these responses.
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In an article published in the Journal of the American College of Cardiology by Lakdawala and colleagues (from Dr. Seidman’s laboratory), the researchers identified a new mutation in the tropomyosin gene that induced DCM in two unrelated families. This new missense mutation was identified in two large multigenerational families. At the gene level, the mutation involved the substitution of guanine to adenine (G>A) at residue 688 in the gene encoding alpha-tropomyosin (TPM1). The identified mutation altered an evolutionarily conserved nucleotide. This substitution removed a highly conserved, negatively charged aspartate (D) residue in the protein at position 230 and replaced it with neutral asparagine (N) on the surface of tropomyosin. The mutation was shown to segregate with those affected in both families and, importantly, the mutation was absent in 1,000 control chromosomes. The D230N variant was found to segregate with DCM in two unrelated families, thus further confirming the causality of this mutation for DCM.
The investigators expressed the D230N mutation in an in vitro system and showed the mutation was associated with decreased affinity for calcium and reduced contractility. The clinical picture was interesting, manifesting an age-dependent bimodal whereby individuals developing DCM in childhood had severe disease (often ending in death), whereas those who developed the phenotype in adulthood tended to have a less severe form of disease. Previously, several mutations in tropomyosin have been identified to be associated with HCM rather than DCM.
The molecular pathways activated by mutations that induce either DCM (sarcomeres in series) or HCM (sarcomeres in parallel) are fundamental to the understanding of these inherited diseases and also fundamental to our understanding of the cardiac growth response to acquired diseases. These genetic abnormalities have clearly been demonstrated in animal models to be a molecular trigger for inducing these markedly different cardiac growth responses. Both forms of remodeling occur in response to acquired disorders such as hypertension or MI. The molecular network remains unknown, whereby one mutation gives rise to hypertrophy and a dilated heart vs. another mutation in the same gene induces hypertrophied non-dilated heart.
Analysis of genetic animal models to unravel the pathways leading to these different growth responses should also help to elucidate the molecular mechanisms underlying the transition from the hypertrophied non-dilated heart to the dilated heart with failure.
For more information:
- Lakdawala N. J Am Coll Cardiol. 2010;55:320-329.
Robert Roberts, MD, is the president and CEO of the University of Ottawa Heart Institute and director of the Ruddy Canadian Cardiovascular Genetics Centre at the University of Ottawa Heart Institute. Brandon Roberts, MSc, is a resident at the University of Ottawa Heart Center.