Cardiomyopathy: A Systematic Review of Disease-Causing Mutations in Myosin Heavy Chain 7 and Their Phenotypic Manifestations

Walsh, Roddy; Rutland, Catrin S.; Thomas, Ronald; Loughna, Siobhan

doi:10.1159/000252808

Cited by 112 publications

(98 citation statements)

References 155 publications

(113 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Besides β-cardiac myosin, the other major site in the sarcomere for HCM mutations is the regulatory protein MyBP-C (Buvoli et al, 2008;Seidman and Seidman, 2011;Walsh et al, 2010). MyBP-C is thought to put a break on the contraction of the muscle, which can be regulated by its phosphorylation (Chow et al, 2014;Kensler et al, 2011;Seidman and Seidman, 2000;van Dijk et al, 2014).…”

Section: + -Desensitizing Respectivelymentioning

confidence: 99%

See 1 more Smart Citation

Effects of hypertrophic and dilated cardiomyopathy mutations on power output by human β-cardiac myosin

Spudich

Aksel

Bartholomew

et al. 2016

Journal of Experimental Biology

View full text Add to dashboard Cite

Hypertrophic cardiomyopathy is the most frequently occurring inherited cardiovascular disease, with a prevalence of more than one in 500 individuals worldwide. Genetically acquired dilated cardiomyopathy is a related disease that is less prevalent. Both are caused by mutations in the genes encoding the fundamental forcegenerating protein machinery of the cardiac muscle sarcomere, including human β-cardiac myosin, the motor protein that powers ventricular contraction. Despite numerous studies, most performed with non-human or non-cardiac myosin, there is no clear consensus about the mechanism of action of these mutations on the function of human β-cardiac myosin. We are using a recombinantly expressed human β-cardiac myosin motor domain along with conventional and new methodologies to characterize the forces and velocities of the mutant myosins compared with wild type. Our studies are extending beyond myosin interactions with pure actin filaments to include the interaction of myosin with regulated actin filaments containing tropomyosin and troponin, the roles of regulatory light chain phosphorylation on the functions of the system, and the possible roles of myosin binding protein-C and titin, important regulatory components of both cardiac and skeletal muscles.

show abstract

Section: + -Desensitizing Respectivelymentioning

confidence: 99%

“…There are reported to be more than 300 pathogenic mutations in β-cardiac myosin (Buvoli et al, 2008;Colegrave and Peckham, 2014;Seidman and Seidman, 2001;Walsh et al, 2010). Most of these are HCM mutations in the globular head domain, myosin S1 (Colegrave and Peckham, 2014).…”

mentioning

confidence: 99%

Effects of hypertrophic and dilated cardiomyopathy mutations on power output by human β-cardiac myosin

Spudich

Aksel

Bartholomew

et al. 2016

Journal of Experimental Biology

View full text Add to dashboard Cite

show abstract

“…2 Telethon Institute of Genetics and Medicine, Naples, Italy. 3 Unit of Pediatric Neurology and Muscular Disorders, Istituto G.Gaslini, Genoa, Italy.…”

Section: Additional Filesmentioning

confidence: 99%

MYH7-related myopathies: Clinical, histopathological and imaging findings in a cohort of Italian patients

Savarese

Astrea

Cassandrini

et al. 2015

Neuromuscular Disorders

View full text Add to dashboard Cite

Background: Myosin heavy chain 7 (MYH7)-related myopathies are emerging as an important group of muscle diseases of childhood and adulthood, with variable clinical and histopathological expression depending on the type and location of the mutation. Mutations in the head and neck domains are a well-established cause of hypertrophic cardiomyopathy whereas mutation in the distal regions have been associated with a range of skeletal myopathies with or without cardiac involvement, including Laing distal myopathy and Myosin storage myopathy. Recently the spectrum of clinical phenotypes associated with mutations in MYH7 has increased, blurring this scheme and adding further phenotypes to the list. A broader disease spectrum could lead to misdiagnosis of different congenital myopathies, neurogenic atrophy and other neuromuscular conditions. Results: As a result of a multicenter Italian study we collected clinical, histopathological and imaging data from a population of 21 cases from 15 families, carrying reported or novel mutations in MYH7. Patients displayed a variable phenotype including atypical pictures, as dropped head and bent spine, which cannot be classified in previously described groups. Half of the patients showed congenital or early infantile weakness with predominant distal weakness. Conversely, patients with later onset present prevalent proximal weakness. Seven patients were also affected by cardiomyopathy mostly in the form of non-compacted left ventricle. Muscle biopsy was consistent with minicores myopathy in numerous cases. Muscle MRI was meaningful in delineating a shared pattern of selective involvement of tibialis anterior muscles, with relative sparing of quadriceps. Conclusion: This work adds to the genotype-phenotype correlation of MYH7-relatedmyopathies confirming the complexity of the disorder.

show abstract

“…[47][48][49] Mutations in the MYH7 gene are commonly found in patients experiencing hypertrophic and dilated cardiomyopathy. 50,51 Most of these mutations affect the globular head region of the myosin molecule. In contrast, MYH7 mutations associated with skeletal muscle myosin storage myopathy with and without cardiomyopathy have almost exclusively been identified in the MYH7 C-terminal rod domain.…”

Section: Myomasp/lrrc39 As a Candidate Gene For Cardiomyopathymentioning

confidence: 99%

Myomasp/LRRC39, a Heart- and Muscle-Specific Protein, Is a Novel Component of the Sarcomeric M-Band and Is Involved in Stretch Sensing

Will

Eden

Just

et al. 2010

Circulation Research

View full text Add to dashboard Cite

Rationale and Objective:The M-band represents a transverse structure in the center of the sarcomeric A-band and provides an anchor for the myosin-containing thick filaments. In contrast to other sarcomeric structures, eg, the Z-disc, only few M-band-specific proteins have been identified to date, and its exact molecular composition remains unclear. Methods and Results:Using a bioinformatic approach to identify novel heart-and muscle-specific genes, we found a leucine rich protein, myomasp (Myosin-interacting, M-band-associated stress-responsive protein)/ LRRC39. RT-PCR and Northern and Western blot analyses confirmed a cardiac-enriched expression pattern, and immunolocalization of myomasp revealed a strong and specific signal at the sarcomeric M-band. Yeast 2-hybrid screens, as well as coimmunoprecipitation experiments, identified the C terminus of myosin heavy chain (MYH)7 as an interaction partner for myomasp. Knockdown of myomasp in neonatal rat ventricular myocytes (NRVCMs) led to a significant upregulation of the stretch-sensitive genes GDF-15 and BNP. Conversely, the expression of MYH7 and the M-band proteins myomesin-1 and -2 was found to be markedly reduced. Mechanistically, knockdown of myomasp in NRVCM led to a dose-dependent suppression of serum response factor-dependent gene expression, consistent with earlier observations linking the M-band to serum response factor-mediated signaling. Finally, downregulation of myomasp/LRRC39 in spontaneously beating engineered heart tissue constructs resulted in significantly lower force generation and reduced fractional shortening. Likewise, knockdown of the myomasp/LRRC39 ortholog in zebrafish resulted in severely impaired heart function and cardiomyopathy in vivo. Key Words: myocytes Ⅲ cardiac Ⅲ stretch Ⅲ serum response factor Ⅲ M-band T he sarcomeres of cardiac and skeletal muscle represent the basic molecular unit for contractile force generation and transmission. 1 The thin filaments of the sarcomere consist of actin fibers that are crosslinked at the Z-disc, whereas the thick filaments, mainly composed of myosin molecules, are attached to the M-band, which provides lateral stabilization. 2 Beyond a mere mechanical function, these crucial subsarcomeric structures and their molecular components have been implicated in the regulation of the dynamics of muscle contraction and the sensing of cardiomyocyte stress. 3,4 Moreover, the sarcomeric Z-disc, as well as the M-band, has increasingly been recognized as a hub for signaling pathways that mediate diverse intracellular processes including cell growth and differentiation, as well as protein turnover and gene expression. 2,4 -6 At the level of the sarcomeric Z-disc, the conversion of structural and mechanical demands to gene transcription is mediated by several specific pathways, including calcium-dependent signaling via the calcineurin- NFATc pathway, 7-9 extracellular signal-regulated kinase 2, 10 protein kinase C, 11 and the ubiquitin modification machinery (eg, via MURF-ligases). 12,13 More recently, the ...

show abstract

Cardiomyopathy: A Systematic Review of Disease-Causing Mutations in Myosin Heavy Chain 7 and Their Phenotypic Manifestations

Cited by 112 publications

References 155 publications

Effects of hypertrophic and dilated cardiomyopathy mutations on power output by human β-cardiac myosin

Effects of hypertrophic and dilated cardiomyopathy mutations on power output by human β-cardiac myosin

MYH7-related myopathies: Clinical, histopathological and imaging findings in a cohort of Italian patients

Myomasp/LRRC39, a Heart- and Muscle-Specific Protein, Is a Novel Component of the Sarcomeric M-Band and Is Involved in Stretch Sensing

Contact Info

Product

Resources

About