2. Academic Validation
  3. A POGLUT1 mutation causes a muscular dystrophy with reduced Notch signaling and satellite cell loss

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

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 cparadas@us.es.
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.

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