Myosinspeichermyopathie: eine seltene Unterform der Proteinaggregationsmyopathien

Kiphuth, Ines-Christine; Neuen-Jacob, Eva; Struffert, Tobias; Wehner, Maria; Wallefeld, William; Laing, Nakita; Schröder, Rolf

doi:10.1055/s-0029-1245145

Cited by 6 publications

(4 citation statements)

References 16 publications

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“…The mutated residue is located in the outer f position, where the side chains are available to interact with other myosin dimers or other proteins. This mutation has been reported in several unrelated cases, confirming the implication of the R1845W mutation of MYH7 in MSM (Tajsharghi et al, 2003, Laing et al, 2005, Kiphuth et al, 2010, Pegoraro et al, 2007, Shingde et al, 2006. Muscle biopsy in affected individuals demonstrates characteristic subsarcolemmal accumulation of material restricted to type 1 muscle fibres.…”

Section: Introductionsupporting

confidence: 70%

Impaired muscle morphology in a Drosophila model of myosin storage myopathy was suppressed by overexpression of an E3 ubiquitin ligase

Dahl-Halvarsson

Olivé

Pokrzywa

et al. 2020

Disease Models &Amp; Mechanisms

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Myosin is vital for body movement and heart contractility. Mutations in MYH7, encoding slow/ß-cardiac myosin heavy chain, are an important cause of hypertrophic and dilated cardiomyopathy, as well as skeletal muscle disease. A dominant missense mutation (R1845W) in MYH7 has been reported in several unrelated cases with myosin storage myopathy. We have developed a Drosophila model for a myosin storage myopathy in order to investigate the dose-dependent mechanisms underlying the pathological roles of R1845W mutation. This study shows that higher expression level of the mutated allele is concomitant with severe impairment of muscle function and progressively disrupted muscle morphology. The impaired muscle morphology associated with the mutant allele was supressed by expression of Abba/Thin, an E3 ubiquitin ligase.This Drosophila model recapitulates pathological features seen in myopathy patients with the R1845W mutation and severe ultrastructural abnormalities including extensive loss of thick filaments with selective A-band loss and preservation of I-band and Z-disks were observed in indirect flight muscles of flies with exclusive expression of mutant myosin. Further, the impaired muscle morphology associated with the mutant allele was supressed by expression of Abba/Thin, an E3 ubiquitin ligase. These findings suggest that modification of ubiquitin proteasome system may be beneficial in myosin storage myopathy by reducing the impact of MYH7 mutation in patients.

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Section: Introductionsupporting

confidence: 70%

Impaired muscle morphology in a Drosophila model of myosin storage myopathy was suppressed by overexpression of an E3 ubiquitin ligase

Dahl-Halvarsson

Olivé

Pokrzywa

et al. 2020

Disease Models &Amp; Mechanisms

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“…This mutation has been reported in several unrelated cases indicating that the C nucleotide at position 5533 is a mutational hotspot [32, 34, 55, 65, 76]. Two additional dominant missense mutations, H1901L [10] and L1793P [22], have later been reported to cause myosin storage myopathy.…”

Section: Myopathies Associated With Slow/beta Myhc Myh7mentioning

confidence: 99%

Myosinopathies: pathology and mechanisms

2012

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The myosin heavy chain (MyHC) is the molecular motor of muscle and forms the backbone of the sarcomere thick filaments. Different MyHC isoforms are of importance for the physiological properties of different muscle fiber types. Hereditary myosin myopathies have emerged as an important group of diseases with variable clinical and morphological expression depending on the mutated isoform and type and location of the mutation. Dominant mutations in developmental MyHC isoform genes (MYH3 and MYH8) are associated with distal arthrogryposis syndromes. Dominant or recessive mutations affecting the type IIa MyHC (MYH2) are associated with early-onset myopathies with variable muscle weakness and ophthalmoplegia as a consistent finding. Myopathies with scapuloperoneal, distal or limb-girdle muscle weakness including entities, such as myosin storage myopathy and Laing distal myopathy are the result of usually dominant mutations in the gene for slow/β cardiac MyHC (MYH7). Protein aggregation is part of the features in some of these myopathies. In myosin storage myopathy protein aggregates are formed by accumulation of myosin beneath the sarcolemma and between myofibrils. In vitro studies on the effects of different mutations associated with myosin storage myopathy and Laing distal myopathy indicate altered biochemical and biophysical properties of the light meromyosin, which is essential for thick filament assembly. Protein aggregates in the form of tubulofilamentous inclusions in association with vacuolated muscle fibers are present at late stage of dominant myosin IIa myopathy and sometimes in Laing distal myopathy. These protein aggregates exhibit features indicating defective degradation of misfolded proteins. In addition to protein aggregation and muscle fiber degeneration some of the myosin mutations cause functional impairment of the molecular motor adding to the pathogenesis of myosinopathies.

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“…The MYH7 gene is composed of 40 exons. In particular, mutations that cause MSM are located in exons 37–40 of MYH7 [ 29 , 30 ].…”

Section: Discussionmentioning

confidence: 99%

A novel heterozygous missense MYH7 mutation potentially causes an autosomal dominant form of myosin storage myopathy with dilated cardiomyopathy

Naderi,

Mohsen-Pour,

Nilipour

et al. 2023

BMC Cardiovasc Disord

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Background The MYH7 gene, which encodes the slow/ß-cardiac myosin heavy chain, is mutated in myosin storage myopathy (MSM). The clinical spectrum of MSM is quite heterogeneous in that it ranges from cardiomyopathies to skeletal myopathies or a combination of both, depending on the affected region. In this study, we performed clinical and molecular examinations of the proband of an Iranian family with MSM in an autosomal dominant condition exhibiting proximal muscle weakness and dilated cardiomyopathy. Methods Following thorough clinical and paraclinical examinations, whole-exome sequencing `was performed on the proband (II-5). Pathogenicity prediction of the candidate variant was performed through in-silico analysis. Co-segregation analysis of the WES data among the family members was carried out by PCR-based Sanger sequencing. Results A novel heterozygous missense variant, MYH7 (NM_000257): c.C1888A: p.Pro630Thr, was found in the DNA of the proband and his children and confirmed by Sanger sequencing. The in-silico analysis revealed that p.Pro630Thr substitution was deleterious. The novel sequence variant fell within a highly conserved region of the head domain. Our findings expand the spectrum of MYH7 mutations. Conclusions This finding could improve genetic counseling and prenatal diagnosis in families with clinical manifestations associated with MYH7-related myopathy.

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Myosinspeichermyopathie: eine seltene Unterform der Proteinaggregationsmyopathien

Cited by 6 publications

References 16 publications

Impaired muscle morphology in a Drosophila model of myosin storage myopathy was suppressed by overexpression of an E3 ubiquitin ligase

Impaired muscle morphology in a Drosophila model of myosin storage myopathy was suppressed by overexpression of an E3 ubiquitin ligase

Myosinopathies: pathology and mechanisms

A novel heterozygous missense MYH7 mutation potentially causes an autosomal dominant form of myosin storage myopathy with dilated cardiomyopathy

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