A POGLUT1 mutation causes a muscular dystrophy with reduced Notch signaling and satellite cell loss

Emilia Servián-Morilla, Hideyuki Takeuchi, Tom V. Lee, Jordi Clarimon, Fabiola Mavillard, Estela Area-Gómez, Eloy Rivas, Jose L. Nieto-González, Maria C. Rivero, Macarena Cabrera-Serrano, Leonardo Gómez-Sánchez, Jose A. Martínez-López, Beatriz Estrada, Celedonio Márquez, Yolanda Morgado, Xavier Suárez-Calvet, Guillermo Pita, Anne Bigot, Eduard Gallardo, Rafael Fernández-ChacónMichio Hirano, Robert S. Haltiwanger, Hamed Jafar-Nejad, Carmen Paradas

    Research output: Contribution to journalArticleResearchpeer-review

    44 Citations (Scopus)

    Abstract

    © 2016 The Authors. Published under the terms of the CC BY 4.0 license Skeletal muscle regeneration by muscle satellite cells is a physiological mechanism activated upon muscle damage and regulated by Notch signaling. In a family with autosomal recessive limb-girdle muscular dystrophy, we identified a missense mutation in POGLUT1 (protein O-glucosyltransferase 1), an enzyme involved in Notch posttranslational modification and function. In vitro and in vivo experiments demonstrated that the mutation reduces O-glucosyltransferase activity on Notch and impairs muscle development. Muscles from patients revealed decreased Notch signaling, dramatic reduction in satellite cell pool and a muscle-specific α-dystroglycan hypoglycosylation not present in patients' fibroblasts. Primary myoblasts from patients showed slow proliferation, facilitated differentiation, and a decreased pool of quiescent PAX7+ cells. A robust rescue of the myogenesis was demonstrated by increasing Notch signaling. None of these alterations were found in muscles from secondary dystroglycanopathy patients. These data suggest that a key pathomechanism for this novel form of muscular dystrophy is Notch-dependent loss of satellite cells.
    Original languageEnglish
    Pages (from-to)1289-1309
    JournalEMBO Molecular Medicine
    Volume8
    Issue number11
    DOIs
    Publication statusPublished - 1 Nov 2016

    Keywords

    • muscular dystrophy
    • Notch
    • O-glycosylation
    • POGLUT1
    • satellite cell

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