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.
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DOI：
10.15252/emmm.201505815
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发表时间：
2016-11
影响因子：
11.1
通讯作者：
Paradas C
中科院分区：
文献类型：
--
作者：
Servián-Morilla E;Takeuchi H;Lee TV;Clarimon J;Mavillard F;Area-Gómez E;Rivas E;Nieto-González JL;Rivero MC;Cabrera-Serrano M;Gómez-Sánchez L;Martínez-López JA;Estrada B;Márquez C;Morgado Y;Suárez-Calvet X;Pita G;Bigot A;Gallardo E;Fernández-Chacón R;Hirano M;Haltiwanger RS;Jafar-Nejad H;Paradas C
骨骼肌卫星细胞再生是骨骼肌损伤后受Notch信号调控的一种生理机制。在一个患有常染色体隐性肢带型肌营养不良症的家族中，我们发现了POGLUT 1（蛋白质O-葡萄糖基转移酶1）的错义突变，POGLUT 1是一种参与Notch翻译后修饰和功能的酶。体外和体内实验表明，该突变降低了Notch上的O-葡萄糖基转移酶活性，并损害了肌肉发育。患者的肌肉显示Notch信号传导减少，卫星细胞池急剧减少，患者成纤维细胞中不存在肌肉特异性α肌营养不良聚糖低糖基化。患者的原代成肌细胞增殖缓慢，易于分化，静止PAX 7+细胞池减少。通过增加Notch信号传导证实了对肌生成的稳健拯救。在继发性肌营养不良症患者的肌肉中没有发现这些改变。这些数据表明，这种新型肌营养不良症的关键病理机制是Notch依赖性卫星细胞丢失。
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.
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DOI：
10.1083/jcb.122.4.809
发表时间：
1993-08
期刊：
The Journal of cell biology
影响因子：
--
作者：
Ervasti JM;Campbell KP
通讯作者：
Campbell KP
DOI：
10.1093/brain/aws312
发表时间：
2013-01
期刊：
Brain : a journal of neurology
影响因子：
--
作者：
Cirak S;Foley AR;Herrmann R;Willer T;Yau S;Stevens E;Torelli S;Brodd L;Kamynina A;Vondracek P;Roper H;Longman C;Korinthenberg R;Marrosu G;Nürnberg P;UK10K Consortium;Michele DE;Plagnol V;Hurles M;Moore SA;Sewry CA;Campbell KP;Voit T;Muntoni F
通讯作者：
Muntoni F
影响因子：
4.5
作者：
Haltom AR;Lee TV;Harvey BM;Leonardi J;Chen YJ;Hong Y;Haltiwanger RS;Jafar-Nejad H
通讯作者：
Jafar-Nejad H
影响因子：
11.8
作者：
Conboy, IM;Rando, TA
通讯作者：
Rando, TA
影响因子：
64.8
作者：
通讯作者：
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