Article

Mutations in the β-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: 9.81). 03/2009; 106(15):6291-6. DOI: 10.1073/pnas.0900107106
Source: PubMed

ABSTRACT 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, Sep 02, 2015
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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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    ABSTRACT: The congenital myopathies are a diverse group of genetic skeletal muscle diseases, which typically present at birth or in early infancy. There are multiple modes of inheritance and degrees of severity (ranging from foetal akinesia, through lethality in the newborn period to milder early and later onset cases). Classically, the congenital myopathies are defined by skeletal muscle dysfunction and a non-dystrophic muscle biopsy with the presence of one or more characteristic histological features. However, mutations in multiple different genes can cause the same pathology and mutations in the same gene can cause multiple different pathologies. This is becoming ever more apparent now that, with the increasing use of next generation sequencing, a genetic diagnosis is achieved for a greater number of patients. Thus, considerable genetic and pathological overlap is emerging, blurring the classically established boundaries. At the same time, some of the pathophysiological concepts underlying the congenital myopathies are moving into sharper focus. Here we explore whether our emerging understanding of disease pathogenesis and underlying pathophysiological mechanisms, rather than a strictly gene-centric approach, will provide grounds for a different and perhaps complementary grouping of the congenital myopathies, that at the same time could help instil the development of shared potential therapeutic approaches. Stemming from recent advances in the congenital myopathy field, five key pathophysiology themes have emerged: defects in (i) sarcolemmal and intracellular membrane remodelling and excitation-contraction coupling; (ii) mitochondrial distribution and function; (iii) myofibrillar force generation; (iv) atrophy; and (v) autophagy. Based on numerous emerging lines of evidence from recent studies in cell lines and patient tissues, mouse models and zebrafish highlighting these unifying pathophysiological themes, here we review the congenital myopathies in relation to these emerging pathophysiological concepts, highlighting both areas of overlap between established entities, as well as areas of distinction within single gene disorders. Published by Oxford University Press on behalf of the Guarantors of Brain 2014. This work is written by US Government employees and is in the public domain in the US.
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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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    • "Biochemical and biophysical characterization of the effects of the myosin storage myopathy mutations in the LMM region have suggested adverse effects of the mutations in the ability of the protein to form stable and functional thick filaments [4]. However, analyses of different mutations demonstrated that each mutation has a unique effect on the biochemical and biophysical properties of the LMM [4]. The pathogenic mechanisms of the R1500P and L1706P causing Laing early-onset distal myopathy have been investigated by biochemical assays and in different cellular systems [5, 12]. "
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