The Molecular Mechanisms of Mutations in Actin and Myosin that Cause Inherited Myopathy

Marston, Steven B.

doi:10.3390/ijms19072020

Cited by 29 publications

(33 citation statements)

References 113 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Curiously, 1 of the mutations examined here shares these properties; the early onset P710R, suggesting some overlap between the groupings. Intersection of molecular phenotypes among different cardiomyopathies has been observed in studies of thin filament mutations and experiments performed in Drosophila (31,32).…”

Section: Discussionmentioning

confidence: 94%

Myosin motor domains carrying mutations implicated in early or late onset hypertrophic cardiomyopathy have similar properties

Vera

Johnson

Walklate

et al. 2019

Journal of Biological Chemistry

View full text Add to dashboard Cite

Hypertrophic cardiomyopathy (HCM) is a common genetic disorder characterized by left ventricular hypertrophy and cardiac hyper-contractility. Mutations in the β-cardiac myosin heavy chain gene (β-MyHC) are a major cause of HCM, but the specific mechanistic changes to myosin function that lead to this disease remain incompletely understood. Predicting the severity of any β-MyHC mutation is hindered by a lack of detailed examinations at the molecular level. Moreover, because HCM can take ≥20 years to develop, the severity of the mutations must be somewhat subtle. We hypothesized that mutations that result in early onset disease would have more severe changes in function than do later onset mutations. Here, we performed steady-state and transient kinetic analyses of myosins carrying one of seven missense mutations in the motor domain. Of these seven, four were previously identified in early onset cardiomyopathy screens. We used the parameters derived from these analyses to model the ATP-driven cross-bridge cycle. Contrary to our hypothesis, the results indicated no clear differences between early and late onset HCM mutations. Despite the lack of distinction between early and late onset HCM, the predicted occupancy of the force-holding actin·myosin·ADP complex at [Actin] = 3 Kapp along with the closely related duty ratio (the fraction of myosin in strongly attached force-holding states), and the measured ATPases all changed in parallel (in both sign and degree of change) compared with wildtype (WT) values. Six of the seven HCM mutations were clearly distinct from a set of previously characterized DCM mutations.

show abstract

Section: Discussionmentioning

confidence: 94%

Myosin motor domains carrying mutations implicated in early or late onset hypertrophic cardiomyopathy have similar properties

Vera

Johnson

Walklate

et al. 2019

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Although most patients present with muscle hypotonia, there are rare patients with muscle hypertonia and a stiff gait (Marttila et al 2014; Davidson et al 2013), thought to stem from higher than normal calcium sensitivity (Jain et al 2012; Donkervoort et al 2015; Marston 2018). Muscle weakness is usually generalised, with involvement of the neck flexors, the face and proximal muscles, often with a later, additional distal involvement.…”

Section: Clinical Featuresmentioning

confidence: 99%

Nemaline myopathies: a current view

Sewry

Laitila

Wallgren‐Pettersson

2019

J Muscle Res Cell Motil

140

133

View full text Add to dashboard Cite

Nemaline myopathies are a heterogenous group of congenital myopathies caused by de novo, dominantly or recessively inherited mutations in at least twelve genes. The genes encoding skeletal α-actin (ACTA1) and nebulin (NEB) are the commonest genetic cause. Most patients have congenital onset characterized by muscle weakness and hypotonia, but the spectrum of clinical phenotypes is broad, ranging from severe neonatal presentations to onset of a milder disorder in childhood. Most patients with adult onset have an autoimmune-related myopathy with a progressive course. The wide application of massively parallel sequencing methods is increasing the number of known causative genes and broadening the range of clinical phenotypes. Nemaline myopathies are identified by the presence of structures that are rod-like or ovoid in shape with electron microscopy, and with light microscopy stain red with the modified Gömöri trichrome technique. These rods or nemaline bodies are derived from Z lines (also known as Z discs or Z disks) and have a similar lattice structure and protein content. Their shape in patients with mutations in KLHL40 and LMOD3 is distinctive and can be useful for diagnosis. The number and distribution of nemaline bodies varies between fibres and different muscles but does not correlate with severity or prognosis. Additional pathological features such as caps, cores and fibre type disproportion are associated with the same genes as those known to cause the presence of rods. Animal models are advancing the understanding of the effects of various mutations in different genes and paving the way for the development of therapies, which at present only manage symptoms and are aimed at maintaining muscle strength, joint mobility, ambulation, respiration and independence in the activities of daily living.

show abstract

“…The Cterminal domains of MyBP-C are anchored to titin (4) and myosin light meromyosin (5), while the Nterminal domains interact with myosin subfragment 2 and probably also with actin (6). Genetic mutation or a post-translational modification (e.g., oxidation, glycation) of a sarcomeric protein can alter its structure and function and have a detrimental effect on the process of contractility (7,8). The binding of a small molecule to that altered protein can restore normal contractility (9).…”

Section: Introductionmentioning

confidence: 99%

Actin-binding compounds, previously discovered by FRET-based high-throughput screening, differentially affect skeletal and cardiac muscle

Guhathakurta

Phung

Próchniewicz

et al. 2020

Journal of Biological Chemistry

View full text Add to dashboard Cite

Actin’s interactions with myosin and other actin-binding proteins is essential for cellular viability in numerous cell types, including muscle. In a previous high-throughput time-resolved fluorescence resonance energy transfer (TR-FRET) screen, we identified a class of compounds that bind to actin and affect actomyosin structure and function. For clinical utility, it is highly desirable to identify compounds that affect skeletal and cardiac muscle differently. Because actin is more highly conserved than myosin and most other muscle proteins, most such efforts have not targeted actin. Nevertheless, in the current study, we tested the specificity of the previously discovered actin-binding compounds for effects on skeletal and cardiac α-actins as well as on skeletal and cardiac myofibrils. We found that a majority of these compounds affected the transition of monomeric G-actin to filamentous F-actin, and that several of these effects were different for skeletal and cardiac actin isoforms. We also found that several of these compounds affected ATPase activity differently in skeletal and cardiac myofibrils. We conclude that these structural and biochemical assays can be used to identify actin-binding compounds that differentially affect skeletal and cardiac muscles. The results of this study set the stage for screening of large chemical libraries for discovery of novel compounds that act therapeutically and specifically on cardiac or skeletal muscle.

show abstract

The Molecular Mechanisms of Mutations in Actin and Myosin that Cause Inherited Myopathy

Cited by 29 publications

References 113 publications

Myosin motor domains carrying mutations implicated in early or late onset hypertrophic cardiomyopathy have similar properties

Myosin motor domains carrying mutations implicated in early or late onset hypertrophic cardiomyopathy have similar properties

Nemaline myopathies: a current view

Actin-binding compounds, previously discovered by FRET-based high-throughput screening, differentially affect skeletal and cardiac muscle

Contact Info

Product

Resources

About