Servian‐Morilla, E., Takeuchi, H., Lee, T.V., Clarimon, J., Mavillard, F., Area‐Gomez, E., Rivas, E., Nieto‐Gonzalez, J.L., Rivero, M.C., Cabrera‐Serrano, M., Gomez‐Sanchez, L., Martinez‐Lopez, J.A., Estrada, B., Márquez, C., Morgado, Y., Suarez‐Calvet, X., Pita, G., Bigot, A., Gallardo, E., Fernandez‐Chacon, R., Hirano, M., Haltiwanger, R.S., Jafar‐Nejad, H., Paradas, C. (2016). A POGLUT1 mutation causes a muscular dystrophy with reduced Notch signaling and satellite cell loss.  EMBO Mol. Med. 8(11): 1289--1309.

FBrf0235420

Research paper

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.

PMC5090660 (PMC) (EuropePMC)