A POGLUT1 mutation causes a muscular dystrophy with reduced Notch signaling and satellite cell loss.
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.
Neuromuscular Disorders Unit, Department of Neurology, Instituto de Biomedicina de Sevilla, Hospital U. Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
Emilia
E
Servián-Morilla
Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY, USA.
Hideyuki
H
Takeuchi
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Tom V
TV
Lee
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.|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.
Jordi
J
Clarimon
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.|Department of Medical Physiology and Biophysics, Instituto de Biomedicina de Sevilla, Hospital U. Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain.
Fabiola
F
Mavillard
Department of Neurology, Columbia University Medical Center, New York, NY, USA.
Estela
E
Area-Gómez
Department of Pathology, Instituto de Biomedicina de Sevilla, Hospital U. Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain.
Eloy
E
Rivas
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.|Department of Medical Physiology and Biophysics, Instituto de Biomedicina de Sevilla, Hospital U. Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain.
Jose L
JL
Nieto-González
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.|Department of Medical Physiology and Biophysics, Instituto de Biomedicina de Sevilla, Hospital U. Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain.
Maria C
MC
Rivero
Neuromuscular Disorders Unit, Department of Neurology, Instituto de Biomedicina de Sevilla, Hospital U. Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
Macarena
M
Cabrera-Serrano
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.|Department of Medical Physiology and Biophysics, Instituto de Biomedicina de Sevilla, Hospital U. Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain.
Leonardo
L
Gómez-Sánchez
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.|Department of Medical Physiology and Biophysics, Instituto de Biomedicina de Sevilla, Hospital U. Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain.
Jose A
JA
Martínez-López
Centro Andaluz de Biología del Desarrollo (CABD), Universidad Pablo Olavide, Sevilla, Spain.
Beatriz
B
Estrada
Neuromuscular Disorders Unit, Department of Neurology, Instituto de Biomedicina de Sevilla, Hospital U. Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain.
Celedonio
C
Márquez
Department of Neurology, Hospital U. Valme, Sevilla, Spain.
Yolanda
Y
Morgado
Laboratori de Malalties Neuromusculars, Institut de Recerca de HSCSP, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Raras (CIBERER), Barcelona, Spain.
Xavier
X
Suárez-Calvet
Human Genotyping Unit-CeGen, Spanish National Cancer Research Centre, Madrid, Spain.
Guillermo
G
Pita
UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, Sorbonne Universités, Paris, France.
Anne
A
Bigot
Laboratori de Malalties Neuromusculars, Institut de Recerca de HSCSP, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Raras (CIBERER), Barcelona, Spain.
Eduard
E
Gallardo
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.|Department of Medical Physiology and Biophysics, Instituto de Biomedicina de Sevilla, Hospital U. Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain.
Rafael
R
Fernández-Chacón
Department of Neurology, Columbia University Medical Center, New York, NY, USA.
Michio
M
Hirano
Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY, USA.
Robert S
RS
Haltiwanger
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Hamed
H
Jafar-Nejad
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.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.|Department of Neurology, Columbia University Medical Center, New York, NY, USA.
Carmen
0000-0002-6917-2236
C
Paradas
D001706:Biopsy; D005964:Glucosyltransferases / Q000235:genetics*; D006031:Glycosylation; D016695:Glycosyltransferases / Q000378:metabolism; D006801:Humans; D009132:Muscles / Q000473:pathology; D009136:Muscular Dystrophies / Q000235:genetics* / Q000473:pathology*; D009154:Mutation; D051880:Receptors, Notch / Q000378:metabolism*; D032496:Satellite Cells, Skeletal Muscle / Q000473:pathology*; D017422:Sequence Analysis, DNA; D015398:Signal Transduction; D013030:Spain
D051880:Receptors, Notch; D016695:Glycosyltransferases; D005964:Glucosyltransferases; C510651:POGLUT1 protein, human
Notch; O‐glycosylation; POGLUT1; muscular dystrophy; satellite cell