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. doi: 10.15252/emmm.201505815. Print 2016 Nov.


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.

Keywords: Notch; O‐glycosylation; POGLUT1; muscular dystrophy; satellite cell.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biopsy
  • Glucosyltransferases / genetics*
  • Glycosylation
  • Glycosyltransferases / metabolism
  • Humans
  • Muscles / pathology
  • Muscular Dystrophies / genetics*
  • Muscular Dystrophies / pathology*
  • Mutation*
  • Receptors, Notch / metabolism*
  • Satellite Cells, Skeletal Muscle / pathology*
  • Sequence Analysis, DNA
  • Signal Transduction*
  • Spain


  • Receptors, Notch
  • Glycosyltransferases
  • Glucosyltransferases
  • POGLUT1 protein, human