Servian-Morilla, EmiliaTakeuchi, HideyukiLee, Tom VClarimon, JordiMavillard, FabiolaArea-Gomez, EstelaRivas, EloyNieto-Gonzalez, Jose LRivero, Maria CCabrera-Serrano, MacarenaGomez-Sanchez, LeonardoMartinez-Lopez, Jose AEstrada, BeatrizMarquez, CeledonioMorgado, YolandaSuarez-Calvet, XavierPita, GuillermoBigot, AnneGallardo, EduardFernandez-Chacon, RafaelHirano, MichioHaltiwanger, Robert SJafar-Nejad, HamedParadas, Carmen2023-01-252023-01-252016-11-02Servián-Morilla E, Takeuchi H, Lee TV, Clarimon J, Mavillard F, Area-Gómez E, et al. A POGLUT1 mutation causes a muscular dystrophy with reduced Notch signaling and satellite cell loss. EMBO Mol Med. 2016 Nov 2;8(11):1289-1309.http://hdl.handle.net/10668/10574Skeletal 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.enAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/NotchO‐glycosylationPOGLUT1muscular dystrophysatellite cellBiopsyGlucosyltransferasesGlycosylationGlycosyltransferasesHumansMusclesMuscular DystrophiesMutationReceptors, NotchSatellite Cells, Skeletal MuscleSequence Analysis, DNASignal TransductionSpainresearch article27807076open accessCélulasGlucosiltransferasasNave espacialDesarrollo de músculosMutación MissenseTécnicas In VitroMioblastos10.15252/emmm.2015058151757-4684PMC5090660https://doi.org/10.15252/emmm.201505815https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5090660/pdf