Japanese multiple epidermal growth factor 10 (MEGF10) myopathy with novel mutations: A phenotype–genotype correlation

Takayama, K.; Mitsuhashi, Satomi; Shin, Je-Young; Tanaka, Rieko; Fujii, Tatsuya; Tsuburaya, Ryuji; Mukaida, Souichi; Noguchi, S.; Nonaka, Ikuya; Nishino, Ichizo

doi:10.1016/j.nmd.2016.06.005

Cited by 15 publications

(21 citation statements)

References 7 publications

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“…Variable combinations of scoliosis, spinal rigidity, multiple, mainly distal contractures and an associated cardiomyopathy may occur in TTN-and MYH7-related forms 20,25 . MEGF10-related myopathies are associated with a very wide spectrum, ranging from a severe early-onset myopathy with areflexia, respiratory distress and dysphagia (termed EMARDD) 21,23,24 to adult-onset cases with minicores on muscle biopsy 22 . Muscle MRI may help to differentiate genetically distinct core myopathies 28,29 .…”

Section: Congenital Myopathies With Cores -Ccd MMD and Mhmentioning

confidence: 99%

Congenital myopathies: disorders of excitation–contraction coupling and muscle contraction

et al. 2018

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The congenital myopathies are a group of early-onset, non-dystrophic neuromuscular conditions with characteristic muscle biopsy findings, variable severity and a stable or slowly progressive course. Pronounced weakness in axial and proximal muscle groups is a common feature, and involvement of extraocular, cardiorespiratory and/or distal muscles can implicate specific genetic defects. Central core disease (CCD), multi-minicore disease (MmD), centronuclear myopathy (CNM) and nemaline myopathy were among the first congenital myopathies to be reported, and they still represent the main diagnostic categories. However, these entities seem to belong to a much wider phenotypic spectrum. To date, congenital myopathies have been attributed to mutations in over 20 genes, which encode proteins implicated in skeletal muscle Ca homeostasis, excitation-contraction coupling, thin-thick filament assembly and interactions, and other mechanisms. RYR1 mutations are the most frequent genetic cause, and CCD and MmD are the most common subgroups. Next-generation sequencing has vastly improved mutation detection and has enabled the identification of novel genetic backgrounds. At present, management of congenital myopathies is largely supportive, although new therapeutic approaches are reaching the clinical trial stage.

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Section: Congenital Myopathies With Cores -Ccd MMD and Mhmentioning

confidence: 99%

Congenital myopathies: disorders of excitation–contraction coupling and muscle contraction

et al. 2018

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“…Other genes involved in MmD are MYH7 (Cullup et al, 2012), TTN (Chauveau et al, 2014), MEGF10 (Boyden et al, 2012;Takayama et al, 2016), SECISBP2, ACTA1, ACTN2, CCD78 (Kazamel and Milone, 2019) and, recently, FXR1 (Estañ et al, 2019) (Box 3). Mutations in the dihydropyridine receptor (DHPR) gene CACNA1S (Box 3) also results in the presence of cores in some families (Schartner et al, 2017).…”

Section: Other Genetic Causesmentioning

confidence: 99%

“…Non-ryanodine mutations RYR1 mutations are the major cause of core myopathies and, as such, have been the most widely studied core myopathy mutation in animal models. Nevertheless, MmD is also caused by mutations in SELENON (Ferreiro et al, 2002a;Kazamel and Milone, 2019), MYH7 (Cullup et al, 2012), ACTA1 (Kaindl, 2004), ACTN2 (Lornage et al, 2019), TTN (Chauveau et al, 2014), MEGF10 (Boyden et al, 2012;Takayama et al, 2016), CCDC78 (Kazamel and Milone, 2019) and FXR1 (Estañ et al, 2019) (Box 3), prompting the development of several non-ryanodine core myopathy models.…”

Section: Recessive Ryr1 Modelsmentioning

confidence: 99%

“…Current evidence suggests that altered Ca 2+ transients are involved both in muscle weakness (Treves et al, 2005) and in core formation (Boncompagni et al, 2009). As such, it remains unclear why cores form in MmD cases caused by mutations in genes not involved in Ca 2+ equilibrium, including TTN (Chauveau et al, 2014), MYH7 (Cullup et al, 2012), MEGF10 (Boyden et al, 2012;Takayama et al, 2016), SECISBP2, ACTA1, ACTN2, CCDC78 (Kazamel andMilone, 2019) andFXR1 (Estañ et al, 2019).…”

Section: Mechanism Of Core Formationmentioning

confidence: 99%

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Cored in the act: the use of models to understand core myopathies

Fusto

Moyle

Gilbert

et al. 2019

Disease Models &Amp; Mechanisms

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The core myopathies are a group of congenital myopathies with variable clinical expressionranging from early-onset skeletal-muscle weakness to later-onset disease of variable severitythat are identified by characteristic 'core-like' lesions in myofibers and the presence of hypothonia and slowly or rather non-progressive muscle weakness. The genetic causes are diverse; central core disease is most often caused by mutations in ryanodine receptor 1 (RYR1), whereas multi-minicore disease is linked to pathogenic variants of several genes, including selenoprotein N (SELENON), RYR1 and titin (TTN). Understanding the mechanisms that drive core development and muscle weakness remains challenging due to the diversity of the excitation-contraction coupling (ECC) proteins involved and the differential effects of mutations across proteins. Because of this, the use of representative models expressing a mature ECC apparatus is crucial. Animal models have facilitated the identification of disease progression mechanisms for some mutations and have provided evidence to help explain genotype-phenotype correlations. However, many unanswered questions remain about the common and divergent pathological mechanisms that drive disease progression, and these mechanisms need to be understood in order to identify therapeutic targets. Several new transgenic animals have been described recently, expanding the spectrum of core myopathy models, including mice with patient-specific mutations. Furthermore, recent developments in 3D tissue engineering are expected to enable the study of core myopathy disease progression and the effects of potential therapeutic interventions in the context of human cells. In this Review, we summarize the current landscape of core myopathy models, and assess the hurdles and opportunities of future modeling strategies.

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“…The classic EMARDD phenotype has a severe congenital onset with high mortality (1,3). Later onset, milder variants of MEGF10 myopathy have been described (6,7). The EMARDD phenotype bears some phenotypic resemblances to the motor neuron disease spinal muscular atrophy (SMA), especially the subtype spinal muscular atrophy with respiratory distress type 1 (SMARD1); however, the primary pathology in MEGF10 myopathy originates in skeletal muscle rather than the motor neurons.…”

Section: Introductionmentioning

confidence: 99%

Selective serotonin reuptake inhibitors ameliorate MEGF10 myopathy

Saha

Rizzo

Ramanathan

et al. 2019

Human Molecular Genetics

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MEGF10 myopathy is a rare inherited muscle disease that is named after the causative gene, MEGF10. The classic phenotype, early onset myopathy, areflexia, respiratory distress and dysphagia, is severe and immediately life-threatening. There are no disease-modifying therapies. We performed a small molecule screen and follow-up studies to seek a novel therapy. A primary in vitro drug screen assessed cellular proliferation patterns in Megf10-deficient myoblasts. Secondary evaluations were performed on primary screen hits using myoblasts derived from Megf10−/− mice, induced pluripotent stem cell-derived myoblasts from MEGF10 myopathy patients, mutant Drosophila that are deficient in the homologue of MEGF10 (Drpr) and megf10 mutant zebrafish. The screen yielded two promising candidates that are both selective serotonin reuptake inhibitors (SSRIs), sertraline and escitalopram. In depth follow-up analyses demonstrated that sertraline was highly effective in alleviating abnormalities across multiple models of the disease including mouse myoblast, human myoblast, Drosophila and zebrafish models. Sertraline also restored deficiencies of Notch1 in disease models. We conclude that SSRIs show promise as potential therapeutic compounds for MEGF10 myopathy, especially sertraline. The mechanism of action may involve the Notch pathway.

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Japanese multiple epidermal growth factor 10 (MEGF10) myopathy with novel mutations: A phenotype–genotype correlation

Cited by 15 publications

References 7 publications

Congenital myopathies: disorders of excitation–contraction coupling and muscle contraction

Congenital myopathies: disorders of excitation–contraction coupling and muscle contraction

Cored in the act: the use of models to understand core myopathies

Selective serotonin reuptake inhibitors ameliorate MEGF10 myopathy

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