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.
Emilia Servián-Morilla  1  2 ,  Hideyuki Takeuchi  3 ,  Tom V Lee  4 ,  Jordi Clarimon  2  5 ,  Fabiola Mavillard  2  6 ,  Estela Area-Gómez  7 ,  Eloy Rivas  8 ,  Jose L Nieto-González  2  6 ,  Maria C Rivero  2  6 ,  Macarena Cabrera-Serrano  1  2 ,  Leonardo Gómez-Sánchez  2  6 ,  Jose A Martínez-López  2  6 ,  Beatriz Estrada  9 ,  Celedonio Márquez  1 ,  Yolanda Morgado  10 ,  Xavier Suárez-Calvet  11  12 ,  Guillermo Pita  13 ,  Anne Bigot  14 ,  Eduard Gallardo  11  12 ,  Rafael Fernández-Chacón  2  6 ,  Michio Hirano  7 ,  Robert S Haltiwanger  3 ,  Hamed Jafar-Nejad  4 ,  Carmen Paradas  15  2  7
Affiliations
  • 1. Neuromuscular Disorders Unit, Department of Neurology, Instituto de Biomedicina de Sevilla, Hospital U. Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain.
  • 2. Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
  • 3. Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY, USA.
  • 4. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
  • 5. Memory Unit, Department of Neurology and Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.
  • 6. Department of Medical Physiology and Biophysics, Instituto de Biomedicina de Sevilla, Hospital U. Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain.
  • 7. Department of Neurology, Columbia University Medical Center, New York, NY, USA.
  • 8. Department of Pathology, Instituto de Biomedicina de Sevilla, Hospital U. Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain.
  • 9. Centro Andaluz de Biología del Desarrollo (CABD), Universidad Pablo Olavide, Sevilla, Spain.
  • 10. Department of Neurology, Hospital U. Valme, Sevilla, Spain.
  • 11. Laboratori de Malalties Neuromusculars, Institut de Recerca de HSCSP, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.
  • 12. Centro de Investigación Biomédica en Red sobre Enfermedades Raras (CIBERER), Barcelona, Spain.
  • 13. Human Genotyping Unit-CeGen, Spanish National Cancer Research Centre, Madrid, Spain.
  • 14. UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, Sorbonne Universités, Paris, France.
  • 15. Neuromuscular Disorders Unit, Department of Neurology, Instituto de Biomedicina de Sevilla, Hospital U. Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain [email protected].
PMID: 27807076 DOI: 10.15252/emmm.201505815
Abstract

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.