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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The Impact of Megf10/Drpr Gain-Of-Function on Muscle Development in DrosophilaI Draper et al. FEBS Lett 593 (7), 680-696. PMID 30802937.Recessive mutations in multiple epidermal growth factor-like domains 10 (MEGF10) underlie a rare congenital muscle disease known as MEGF10 myopathy. MEGF10 and its Drosop …
Consequences of MEGF10 Deficiency on Myoblast Function and Notch1 InteractionsM Saha et al. Hum Mol Genet 26 (15), 2984-3000. PMID 28498977.Mutations in MEGF10 cause early onset myopathy, areflexia, respiratory distress, and dysphagia (EMARDD), a rare congenital muscle disease, but the pathogenic mechanisms r …
Silencing of Drpr Leads to Muscle and Brain Degeneration in Adult DrosophilaI Draper et al. Am J Pathol 184 (10), 2653-61. PMID 25111228.Mutations in the gene encoding the single transmembrane receptor multiple epidermal growth factor-like domain 10 (MEGF10) cause an autosomal recessive congenital muscle d …
MEGF10 Related Myopathies: A New Case With Adult Onset Disease With Prominent Respiratory Failure and Review of Reported PhenotypesE Harris et al. Neuromuscul Disord 28 (1), 48-53. PMID 29128256. - ReviewRecessive mutations in MEGF10 (multiple epidermal growth factor 10) have been reported in a severe early onset disorder named Early Myopathy, Areflexia, Respiratory Distr …
Serotonin Reuptake Inhibitors and Breastfeeding: A Systematic ReviewL Orsolini et al. Hum Psychopharmacol 30 (1), 4-20. PMID 25572308. - ReviewLiterature review clearly indicates paroxetine and sertraline as the drugs that should be preferred as first line choice in nursing women who need an antidepressant treat …