A POGLUT1 mutation causes a muscular dystrophy with reduced Notch signaling and satellite cell loss.
EMBO Mol Med
; 8(11): 1289-1309, 2016 11.
Article
em En
| MEDLINE
| ID: mdl-27807076
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.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
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Células Satélites de Músculo Esquelético
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Receptores Notch
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Glucosiltransferases
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Distrofias Musculares
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Mutação
Tipo de estudo:
Etiology_studies
Limite:
Humans
País/Região como assunto:
Europa
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article