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Myosin at the Heart of the Problem
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     In humans, myosins comprise a superfamily of more than 30 individual proteins. Structurally, myosin contains a highly conserved globular head, which, in turn, contains the ATPase and actin-binding sites, and a rod-like tail that modulates assembly and protein–protein interactions. Although the role of myosin as the molecular motor that drives striated-muscle contraction is well understood, myosins are also found in virtually all eukaryotic cells, where they are involved in a broad range of intracellular functions, including organelle transport, endocytosis, cytokinesis, and cytoskeletal support. In the past 10 years, research in a number of fields has revealed many of the underlying molecular mechanisms that determine how these highly homologous proteins can fulfill such diverse physiological roles. In addition, a parallel series of human genetic studies has revealed that mutations in myosin proteins result in a strikingly broad array of congenital disorders. This clinical heterogeneity appears to reflect the range of physiological functions that myosin fulfills in eukaryotic cells.

    The human myosins can be broadly divided into two groups: "conventional" (class II) myosins form filaments in a hexameric array of two heavy chains and two pairs of light chains, whereas "unconventional" myosins do not form filaments and perform varied functions in a broad range of cells (see Figure). The intracellular role of many of the unconventional myosins remains unclear. In a departure from the more usual approach whereby studies of protein function improve our understanding of disease pathogenesis, recent data from several genetic and clinical studies of human disorders have led to important advances in our understanding of basic myosin function.

    Figure. Conventional (Class II) and Unconventional Myosins.

    Conventional myosins (including the perinatal myosin heavy chain) form filaments by means of an elongated rod-like tail of the protein. The resultant thick filament is incorporated into the sarcomere, where it acts as the molecular motor of muscle contraction. Functional changes are accomplished through isoform switching. Although many of the unconventional myosins are homologous to the class II proteins, the overall structures are different. In the case of myosin VIIa, the short rod-like tail does not form filaments and instead interacts with several structural proteins in several types of cells. These protein complexes determine the varied functional roles of the unconventional myosins.

    Myosins have been implicated in a number of both syndromic and nonsyndromic genetic disorders (see Table). An illustrative example is the role of the unconventional myosin VIIa in the pathogenesis of the type 1B Usher syndrome. The Usher syndrome (sensorineural deafness and progressive retinitis pigmentosa) is the most common cause of deafness and blindness in school-age children. Several of the identified disease genes encode proteins (including myosin VIIa) that interact with one another to ensure the normal organization and stability of the stereocilia within the hair cells of the cochlear inner ear. The role of the myosin VIIa mutations in the development of the associated retinitis pigmentosa is less clear. Recent data, however, have suggested that opsin transport and defects in phagocytosis of the inner rod by pigmented epithelial cells may be involved. Thus, the genetic characterization of the type 1B Usher syndrome has shown how defects in independent functions of myosin-VIIa can lead to complex human syndromes and has led to novel hypotheses regarding myosin-VIIa function.

    Table. Myosin-Related Genetic Disorders.

    There is far less mystery surrounding the physiological roles of conventional myosins — or so it had been thought. The class II myosins are found in both muscle cells and nonmuscle cells and represent approximately one third of all human myosins. In skeletal and cardiac muscle, the myosin heavy chains and their associated light chains act as the molecular motor that drives sarcomeric contraction. Whereas unconventional myosins depend on different functional classes of proteins to achieve their diverse physiological roles, the class II myosins in striated muscle use a complex series of developmentally and physiologically modulated isoform shifts among the highly homologous family members to generate a wide range of muscle phenotypes. Both the integrity of the proteins and the regulation of isoform switching determine the ability of striated muscle to adapt and respond to both normal and pathophysiological stimuli in order to maintain normal contractile function.

    Mutations in the cardiac -myosin heavy-chain isoform in humans have been linked to the development of familial hypertrophic cardiomyopathy, one of the most common cardiac causes of sudden death among young people. The diverse nature of the many mutations in the -myosin heavy chain precludes assigning a single disease mechanism. A large series of in vitro and in vivo studies, however, has led to the hypothesis that the observed ventricular hypertrophy or dilatation is due to abnormalities in force production, energy utilization, or both at the level of the cardiac sarcomere. Subsequent findings with respect to many of the other -myosin heavy-chain mutations have both advanced our knowledge of sarcomeric myosin function and, more recently, suggested that the contractile status of the cardiac sarcomere itself can alter downstream signaling pathways that lead to the development of clinical cardiomyopathies.

    Clearly, the study of the role of myosins in human disease has led to a detailed understanding of a broad array of basic cellular physiological processes. Even so, the main finding presented by Veugelers et al. in this issue of the Journal (pages 460–469) — that a single missense mutation (R674Q) in the perinatal isoform of the myosin heavy-chain gene is associated with a novel heart–hand syndrome characterized by a distal arthrogryposis (the trismus–pseudocamptodactyly syndrome) and the development of cardiac myxomas — is both unexpected and exciting. As the authors note, the observed limb and jaw arthrogryposes may well represent a developmental counterpart to the aforementioned -myosin heavy-chain mutations in cardiac tissue. The severity and specificity of the trismus–pseudocamptodactyly phenotype suggest that both the timing of expression and presumably the incorporation of the perinatal myosin heavy-chain isoform play a crucial role in the normal development of fetal skeletal muscle tendons.

    Although the mechanism or mechanisms underlying the development of the trismus–pseudocamptodactyly syndrome in patients carrying R674Q mutations in the perinatal myosin heavy chain may prove to be relatively straightforward, the causal relationship between the mutation and the development of primary cardiac myxomas is entirely unclear. Quite simply, this result could not have been predicted on the basis of our current knowledge of the functional role of myosin II in striated muscle. In the absence of additional functional data or animal models, any current hypotheses must remain highly speculative. One possibility, however, is that the perinatal myosin heavy chain is an important component of the developmental pathway that determines the number of native cardiac progenitor cells in the developing heart. Perhaps the R674Q mutation in the perinatal myosin heavy chain leads, through an unknown mechanism, to a block in the normal perinatal loss of these multipotent cells so that affected patients end up carrying a larger population through adulthood, with the concomitant increased risk of a "second hit" that would lead to primary cardiac tumorigenesis.

    From the standpoint of both clinical cardiology and basic muscle biology, the novel findings presented in this article clearly raise many more questions than they answer. However, it is abundantly clear that we must once again readjust our thinking and broaden our horizons regarding the multifunctional roles of myosins in human biology.

    Source Information

    From the Departments of Medicine and Physiology and Biophysics, Albert Einstein College of Medicine, Bronx, N.Y.

    Related Letters:

    Mutation of Perinatal Myosin Heavy Chain

    Stratakis C. A., Bertherat J., Carney J. A., Brown M. A., Morita H., Nagai R., Basson C. T., Veugelers M., McDermott D. A.(Jil C. Tardiff, M.D., Ph.)