Mutations in the -myosin rod cause myosin storage myopathy via multiple mechanisms

Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO 80309, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 03/2009; 106(15):6291-6. DOI: 10.1073/pnas.0900107106
Source: PubMed


Myosin storage myopathy (MSM) is a congenital myopathy characterized by the presence of subsarcolemmal inclusions of myosin in the majority of type I muscle fibers, and has been linked to 4 mutations in the slow/cardiac muscle myosin, beta-MyHC (MYH7). Although the majority of the >230 disease causing mutations in MYH7 are located in the globular head region of the molecule, those responsible for MSM are part of a subset of MYH7 mutations that are located in the alpha-helical coiled-coil tail. Mutations in the myosin head are thought to affect the ATPase and actin-binding properties of the molecule. To date, however, there are no reports of the molecular mechanism of pathogenesis for mutations in the rod region of muscle myosins. Here, we present analysis of 4 mutations responsible for MSM: L1793P, R1845W, E1886K, and H1901L. We show that each MSM mutation has a different molecular phenotype, suggesting that there are multiple mechanisms by which MSM can be caused. These mechanisms range from thermodynamic and functional irregularities of individual proteins (L1793P), to varying defects in the assembly and stability of filaments formed from the proteins (R1845W, E1886K, and H1901L). In addition to furthering our understanding of MSM, these observations provide the first insight into how mutations affect the rod region of muscle myosins, and provide a framework for future studies of disease-causing mutations in this region of the molecule.

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Available from: Leslie A Leinwand
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    • "A recent report suggests that MYH7 mutations may be more frequent in the congenital myopathies than previously suggested (Clarke et al., 2013). Typically mutations altering amino acid residues within the globular head domain cause a cardiomyopathy whereas those altering amino acids within the tail rod domain cause a skeletal muscle phenotype (Armel and Leinwand, 2009, 2010); however, in recent years this distinction has become less obvious (Muelas et al., 2010; Homayoun et al., 2011; Lamont et al., 2014). The pathophysiology of MYH7- related cardiomyopathies has begun to be elucidated, the maximum force generating capacity of single cardiac myocytes and isolated myofibrils harbouring MYH7 mutations were lower than controls, even when normalized to cross-sectional area. "
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    Full-text · Article · Dec 2014 · Brain
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    • "Single point mutations in full length LMM (E1356K, L1793P, R1845W, E1886K, H1901L, R1500P, and R1500W) have been shown not to markedly destabilize the structure of a full-length coiled–coil, although they can modify thermal stability (Armel and Leinwand, 2009, 2010a, 2010b). However, other mutations (N1327K, E1356K, R1382W, E1555K, and R1768K and R1500W) investigated in smaller fragments of just a few heptad repeats do affect helicity (Wolny et al., 2013). "
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    Full-text · Article · Sep 2014 · The Anatomical Record Advances in Integrative Anatomy and Evolutionary Biology
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    • "The insertion of proline in a sequence forming a coiled coil very likely explains the observed disease phenotype. These structures have an important role as main structural feature known to dimerize myosins to form the molecular motors of the musclular fiber [12] It has been pointed out that proline is generally destructive for the formation of a coiled coil structure [13] both in the a and d position. Using Marcoil, a software that predicts existence and location of potential coiled-coil domains in protein sequences [14,15], we observed that in comparison to the wild type, the insertion we observed caused a drop to zero of the probability of formation of the coiled coil, suggesting a disruptive effect of the mutation. "
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