A POGLUT1 mutation causes a muscular dystrophy with reduced Notch signaling and satellite cell loss
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- 作者：Emilia Serviá ; n-Morilla ; Hideyuki Takeuchi ; Tom V Lee ; Jordi Clarimon ; Fabiola Mavillard ; Estela Area-Gó ; mez ; Eloy Rivas ; Jose L Nieto-Gonzá ; lez ; Maria C Rivero ; Macarena Cabrera-Serrano ; Leonardo Gó ; mez-Sá ; nchez ; Jose A Martí ; nez-Ló ; pez ; Beatriz Estrada ; Celedonio Má ; rquez ; Yolanda Morgado ; Xavier Suá ; rez-Calvet ; Guillermo Pita ; Anne Bigot ; Eduard Gallardo ; Rafael Ferná ; ndez-Chacó ; n ; Michio Hirano ; Robert S Haltiwanger ; Hamed Jafar-Nejad and Carmen Paradas
- 刊名：EMBO Molecular Medicine
- 出版年：2016
- 出版时间：November 2016
- 年：2016
- 卷：8
- 期：11
- 页码：1289-1309
- 全文大小：4946K
- ISSN：1757-4684
文摘
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.