Mutation of the slow myosin heavy chain rod domain underlies hyaline body myopathy

Bohlega, Saeed; Abu-Amero, S. N.; Wakil, Salma M.; Carroll, Pamela M.; Al-Amr, Rana; Lach, Boleslav; Alsayed, Yazan; Cupler, Edward; Meyer, Brian F.

doi:10.1212/01.wnl.0000123255.92062.37

Cited by 64 publications

(28 citation statements)

References 19 publications

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“…To date, all reported instances of MSM are associated with 1 of 4 mutations in the LMM region of the ␤-MyHC rod (8)(9)(10)(27)(28)(29)(30)(31)(32). By using an array of assays to biochemically and biophysically characterize the effects that these mutations have on the protein, we have found that each mutation possesses a unique molecular phenotype.…”

Section: Discussionmentioning

confidence: 99%

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

Armel

Leinwand

2009

Proc. Natl. Acad. Sci. U.S.A.

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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, ␤-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 ␣-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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Section: Discussionmentioning

confidence: 99%

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

Armel

Leinwand

2009

Proc. Natl. Acad. Sci. U.S.A.

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“…Mutations in the MYH7 gene are also known to cause familial hypertrophic and dilated cardiomyopathy and myosin storage, hyaline body myopathy [8][9][10][11]. Heterozygous mutations in the MYH7 gene causing the Laing myopathy phenotype were previously reported in exons 32, 34, 35, and 36, which corresponds on the protein level to the light meromyosin (LMM) region of the MyHC tail.…”

Section: Discussionmentioning

confidence: 99%

A novel MYH7 mutation occurring independently in French and Norwegian Laing distal myopathy families and de novo in one Finnish patient

et al. 2011

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Laing early-onset distal myopathy is a rare autosomal dominant myopathy and caused by mutations in the MYH7 gene, encoding the slow beta myosin heavy chain. We report the first molecularly verified Laing distal myopathy in a French family caused by a novel p.Glu1508del mutation in the MYH7 gene. Interestingly, we identified the identical mutation in an unrelated Norwegian family and, as a de novo mutation, in one sporadic Finnish patient. Described in detail are the clinical and electrophysiological characteristics of 5 patients from the French family. The phenotype in the Finnish patient and the Norwegian patients is largely similar. This mutation causes a benign myopathy within the range of previously reported Laing myopathy phenotype variations. Onset of weakness in the tibialis anterior (TA) muscles occurred in early childhood in all patients. Finger extensor and neck flexor weakness together with Achilles tendon retractions were other frequent findings. The independent recurrence of the identical mutation without any founder background may reflect a mutational susceptibility of this residue, in accordance with some other MYH7 mutations previously reported. De novo mutations seem to be frequent in Laing distal myopathy. This is of clinical importance since a dominant family history is missing, which may confuse differential diagnostic efforts.

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“…64,65 Interestingly, 17% of these MYH7 mutations lie in the rod of the ␤-myosin heavy chain. 63,66 Other MYH7 rod mutations are also associated with a skeletal myopathy, 67 causing muscle weakness and wasting and hyaline body myopathy 68 (HBM), a congenital neuromuscular disorder. To date, a biochemical explanation of how MYH7 rod mutations impair function to cause these disorders is lacking.…”

Section: Myosin-ii Mutations and Human Pathologymentioning

confidence: 99%

Rod mutations associated with MYH9-related disorders disrupt nonmuscle myosin-IIA assembly

Franke

Fan

Rickoll

et al. 2005

Blood

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MYH9-related disorders are autosomal dominant syndromes, variably affecting platelet formation, hearing, and kidney function, and result from mutations in the human nonmuscle myosin-IIA heavy chain gene. To understand the mechanisms by which mutations in the rod region disrupt nonmuscle myosin-IIA function, we examined the in vitro behavior of 4 common mutant forms of the rod (R1165C, D1424N, E1841K, and R1933Stop) compared with wild type. We used negative-stain electron microscopy to analyze paracrystal morphology, a model system for the assembly of individual myosin-II molecules into bipolar filaments. Wild-type tail fragments formed ordered paracrystal arrays, whereas mutants formed aberrant aggregates. In mixing experiments, the mutants act dominantly to interfere with the proper assembly of wild type. Using circular dichroism, we find that 2 mutants affect the ␣-helical coiled-coil structure of individual molecules, and 2 mutants disrupt the lateral associations among individual molecules necessary to form higher-order assemblies, helping explain the dominant effects of these mutants. These results demonstrate that the most common mutations in MYH9, lesions in the rod, cause defects in nonmuscle myosin-IIA assembly. Further, the application of these methods to biochemically characterize rod mutations could be extended to other myosins responsible for disease. IntroductionThe autosomal dominant, giant-platelet disorders-May-Hegglin anomaly (MHA), Fechtner (FTNS), Sebastian (SBS), Epstein (EPS), and Alport-like syndromes with macrothrombocytopeniasresult from mutations in the human MYH9 gene, which encodes nonmuscle myosin-IIA heavy chain. [1][2][3][4][5] Virtually all patients exhibit platelet macrocytosis, thrombocytopenia, and leukocyte inclusions. Some individuals also exhibit high-tone sensorineural deafness, cataracts, and nephritis to varying degrees. Additional genetic or environmental factors may contribute to the variable penetrance of the nonhematologic clinical manifestations. 6,7 A single family with predominantly hearing loss has been reported. 8 Together, these illnesses represent a spectrum of disorders collectively termed MYH9-related disorders. 6,7,9 Of the 82 mutations identified in MYH9-related disorder families, only 21 amino acids, out of a possible 1961, are mutated. 3,7,10 Identical MYH9 mutations occur in unrelated families and can arise spontaneously, suggesting that these disorders result from highly specific disruption of the MYH9 structure and/or function. Mutations at other sites may occur and remain undetected owing to (1) a completely recessive alteration in myosin-II function, (2) a weakly penetrant dominant effect that escapes clinical detection, or (3) severe dysfunction that is incompatible with life.In humans, the 3 nonmuscle myosin-II heavy chains (IIA, IIB, and IIC) are encoded by distinct genes (MYH9, MYH10, and MYH14, respectively). 11 Only nonmuscle myosin-IIA is expressed in platelets, 12,13 and no mutations in nonmuscle myosin-IIB or myosin-IIC have been reported. ...

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Mutation of the slow myosin heavy chain rod domain underlies hyaline body myopathy

Cited by 64 publications

References 19 publications

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

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

A novel MYH7 mutation occurring independently in French and Norwegian Laing distal myopathy families and de novo in one Finnish patient

Rod mutations associated with MYH9-related disorders disrupt nonmuscle myosin-IIA assembly

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