%0 Journal Article
%A Servian-Morilla, Emilia
%A Takeuchi, Hideyuki
%A Lee, Tom V
%A Clarimon, Jordi
%A Mavillard, Fabiola
%A Area-Gomez, Estela
%A Rivas, Eloy
%A Nieto-Gonzalez, Jose L
%A Rivero, Maria C
%A Cabrera-Serrano, Macarena
%A Gomez-Sanchez, Leonardo
%A Martinez-Lopez, Jose A
%A Estrada, Beatriz
%A Marquez, Celedonio
%A Morgado, Yolanda
%A Suarez-Calvet, Xavier
%A Pita, Guillermo
%A Bigot, Anne
%A Gallardo, Eduard
%A Fernandez-Chacon, Rafael
%A Hirano, Michio
%A Haltiwanger, Robert S
%A Jafar-Nejad, Hamed
%A Paradas, Carmen
%T A POGLUT1 mutation causes a muscular dystrophy with reduced Notch signaling and satellite cell loss.
%D 2016
%U http://hdl.handle.net/10668/10574
%X 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.
%K Notch
%K O‐glycosylation
%K POGLUT1
%K muscular dystrophy
%K satellite cell
%~