Abstract
The discovery that mutations in myosin and actin genes, together with mutations in the other components of the muscle sarcomere, are responsible for a range of inherited muscle diseases (myopathies) has revolutionized the study of muscle, converting it from a subject of basic science to a relevant subject for clinical study and has been responsible for a great increase of interest in muscle studies. Myopathies are linked to mutations in five of the myosin heavy chain genes, three of the myosin light chain genes, and three of the actin genes. This review aims to determine to what extent we can explain disease phenotype from the mutant genotype. To optimise our chances of finding the right mechanism we must study a myopathy where there are a large number of different mutations that cause a common phenotype and so are likely to have a common mechanism: a corollary to this criterion is that if any mutation causes the disease phenotype but does not correspond to the proposed mechanism, then the whole mechanism is suspect. Using these criteria, we consider two cases where plausible genotype-phenotype mechanisms have been proposed: the actin “A-triad” and the myosin “mesa/IHD” models.
Highlights
The discovery that mutations in myosin and actin genes, together with mutations in the other components of the muscle sarcomere, are responsible for a range of inherited muscle diseases has revolutionised the study of muscle, converting it from a subject of basic science to a relevant subject for clinical study and has been responsible for a great increase of interest in muscle studies.We know that myopathies are linked to mutations in five of the myosin heavy chain genes, three of the myosin light chain genes, and three of the actin genes (Table 1)
MyBP-C is associated with the muscle thick filament; it binds to thick filaments through interactions with LMM, S-2 and myosin light chain and binds to actin
A significant number of hypertrophic cardiomyopathy (HCM) patients have a septal myectomy operation to relieve outflow tract obstruction and this can yield a few grams of mutant tissue [45,46]; explanted hearts from dilated cardiomyopathy (DCM) patients with identified causative mutations undergoing heart transplant provides a rare source of tissue for investigation [47,48]
Summary
The discovery that mutations in myosin and actin genes, together with mutations in the other components of the muscle sarcomere, are responsible for a range of inherited muscle diseases (myopathies) has revolutionised the study of muscle, converting it from a subject of basic science to a relevant subject for clinical study and has been responsible for a great increase of interest in muscle studies. One of the reasons for rapid progress in the early days of gene sequencing is the simplicity of their genetics Both myosin and actin are highly conserved proteins, their genes are relatively small, and exon-swapping isoforms are minimal in myosin heavy chain and absent in myosin light chains and actin (compare this with the complexity of tropomyosin, another highly conserved muscle protein [1]). Variants of these proteins are tissue and developmentally specific and are usually transcribed from separate genes [2,3,4,5]. This review aims to determine to what extent we can explain disease phenotype from the mutant genotype
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