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

ABSTRACTMyosin is vital for body movement and heart contractility. Mutations in MYH7, encoding slow/β-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 of 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 the R1845W mutation. This study shows that a 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 suppressed by expression of Thin (herein referred to as Abba), 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. Furthermore, the impaired muscle morphology associated with the mutant allele was suppressed by expression of Abba. These findings suggest that modification of the ubiquitin proteasome system may be beneficial in myosin storage myopathy by reducing the impact of MYH7 mutation in patients.

The association of the Arg1277Gln mutation in the MYH7 gene with myosin storage myopathy in a Chinese family

Background Myosin storage myopathy (MSM) is caused by missense mutations in the MYH7 gene, which encodes the β-cardiac/slow skeletal muscle myosin heavy chain rod (MyHCI). MSM is an autosomal dominant/recessive myopathy characterized by subsarcolemmal accumulations of myosin in type I muscle fibers that results in weakness of the scapula, limb and distal muscles.Methods Here, we report a MSM phenotype that was present across three generations of individuals from the same family, one of whom was a neonate.Results At birth, the neonate had an elevated creatine kinase level and decreased muscle tone in the limbs. At 2 months of age, the infant’s cervical vertebrae caused his head to be skewed to the right. At 7 months of age, the infant’s development was delayed.Whole exome sequencing showed a novel heterozygous variant NM_000257.3: c.3830G>A (p.Arg1277Gln) at exon 28 of the MYH7 gene in the DNA of the infant and his father.Conclusions Previously, which site has only been reported in 2 cases of cardiomyopathy; therefore, this study expands our knowledge of the clinical phenotypes associated with mutations within the rod region of MyHCI. Importantly, close follow-up of the neonate will provide important information on the natural history of MSM associated with MYH7 gene mutation.