As genome and gene sequencing rapidly expand, data increasingly outpace studies linking genetic variants to specific diseases, making computational methods for associating potential mutations with pathology both essential and feasible. We found that disease-causing variants associated with Myosin Storage Myopathy (MSM) generally destabilize the MYH7 α-helical coiled-coil domain more than non-disease-associated variants, and structural mapping revealed that pathogenic variants cluster in locally unwound regions of the coiled-coil dimer, suggesting that changes in these strained sites may promote dimer destabilization and aggregation. However, these features alone are insufficient to reliably predict hereditary Myosin Storage Myopathy. By integrating protein aggregation, structural stability, and additional informative features, we developed RDSM-MYH7, a machine learning-based predictor for assessing the pathogenicity of missense mutations in the MYH7 rod domain. RDSM-MYH7 achieved superior performance (F1 = 0.869, accuracy = 0.875), compared to existing tools, and can be applied to individual gene sequencing data to identify pathogenic MYH7-variants associated with storage myopathy. Its implementation in clinical screening could facilitate early diagnosis of myopathies and other hereditary protein storage diseases, in which protein unfolding precedes pathological aggregation.

Congenital myopathies (CMYOs) encompass a group of genetically heterogeneous rare muscle disorders with clinical features including hypotonia, muscle weakness leading to delayed or absent motor milestones, feeding and respiratory difficulties, and a myopathic facial appearance. CMYO categorisation includes: Nemaline Myopathy, Core Myopathy, Central Core Disease, Multi-Mini Core Disease, Congenital Fiber-type Disproportion Myopathy, Myosin Storage Myopathy, Centronuclear Myopathy, Myotubular Myopathy, X-linked Myotubular Myopathy, and Autosomal Centronuclear Myopathy. The aim of this systematic review is to evaluate the current evidence base of motor outcome measures used in the assessment of CMYO. Methodology was in accordance with the PRISMA 2020 guidelines and registered (PROSPERO CRD42024569701). Databases searched include PubMed, EMBASE, and Cochrane library. Peer reviewed, full-text, English language publications were included. The 31 articles included motor outcome measures of motor function, gross motor, muscle strength, and endurance. Twenty-six motor outcome measures were identified and all were found to have limited disease-specific metrics. This systematic review discussed motor outcome measure suitably in relation to disease characteristics and identified the lack of disease-specificity as the largest gap for future research.

Myosin storage myopathy (MSM) is a rare skeletal muscle disorder caused by mutations in the slow muscle/β-cardiac myosin heavy chain (MHC) gene. MSM missense mutations frequently disrupt the tail's stabilizing heptad repeat motif. Disease hallmarks include subsarcolemmal hyaline-like β-MHC aggregates, muscle weakness, and, occasionally, cardiomyopathy. We generated transgenic, heterozygous Drosophila to examine the dominant physiological and structural effects of the L1793P, R1845W, and E1883K MHC MSM mutations on diverse muscles. The MHC variants reduced lifespan and flight and jump abilities. Moreover, confocal and electron microscopy revealed that they provoked indirect flight muscle breaks and myofibrillar disarray/degeneration with filamentous inclusions. Incorporation of GFP-myosin enabled in situ determination of thick filament lengths, which were significantly reduced in all mutants. Semiautomated heartbeat analysis uncovered aberrant cardiac function, which worsened with age. Thus, our fly models phenocopied traits observed among MSM patients. We additionally mapped the mutations onto a recently determined, 6 Å resolution, cryo-EM structure of the human cardiac thick filament. The R1845W mutation replaces a basic arginine with a polar-neutral, bulkier tryptophan, while E1883K reverses charge at critical filament loci. Both would be expected to disrupt the core and the outer shell of the backbone structure. Replacing L1793 with a proline, a potent breaker of α-helices, could disturb the coiled-coil of the myosin rod and alter the tail-tail interactome. Hence, all mutations likely destabilize and weaken the filament backbone. This may trigger disease in humans, while potentially analogous perturbations are likely to yield the observed thick filament and muscle disruption in our fly models.

Variants in MYH7 cause cardiomyopathies as well as myosin storage myopathy and Laing early-onset distal myopathy (MPD1). MPD1 is characterized by muscle weakness and atrophy usually beginning in the lower legs. Here, we generated iPSC lines from lymphoblastoid cells of three unrelated individuals heterozygous for the most common MPD1-causing variant; p.Lys1617del. iPSC lines showed typical morphology, expressed pluripotency markers, demonstrated trilineage differentiation potential, and had a normal karyotype. These lines represent the first iPSCs derived from MPD1 patients and complement existing MPD1 animal models. They can provide in vitro platforms to better understand and model MPD1 pathomechanisms and test therapies.

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. 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. 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. This finding could improve genetic counseling and prenatal diagnosis in families with clinical manifestations associated with MYH7-related myopathy.