Fukutin is prerequisite to ameliorate muscular dystrophic phenotype by myofiber-selective LARGE expression.
Fukutin is prerequisite to ameliorate muscular dystrophic phenotype by myofiber-selective LARGE expression.
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DOI：
10.1038/srep08316
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发表时间：
2015-02-09
影响因子：
4.6
通讯作者：
Toda T
中科院分区：
文献类型：
--
作者：
Ohtsuka Y;Kanagawa M;Yu CC;Ito C;Chiyo T;Kobayashi K;Okada T;Takeda S;Toda T
α-糖营养不良（α-DGP）是以α-糖营养不良（α-DG）糖基化异常为特征的一组肌营养不良，包括福山先天性肌营养不良（FCMD）、肌眼脑病、Walker-Warburg综合征、先天性1D型肌营养不良（MDC1D）等。MDC1D的致病基因LARGE编码糖基转移酶，在磷酸化后片段末端形成[- 3xyl -α 1,3glca β1-]聚合物，这对α-DG的功能至关重要。有研究表明，无论α- dgp的致病基因如何，LARGE都具有很大的修复α- dgp糖基化缺陷的潜力。然而，使用LARGE活性的体内治疗益处是有争议的。为了探索LARGE基因治疗成功所需的条件，我们分别使用了MDC1D和ffcmd的LARGE缺陷和fukutin缺陷小鼠模型。通过全身腺相关病毒基因转移的肌纤维选择性LARGE表达改善了大缺陷小鼠的营养不良病理，即使在疾病表现后进行干预。然而，同样的策略未能改善富富汀条件敲除小鼠的营养不良表型。此外，在缺乏fukutin的胚胎干细胞中，强制表达Large也未能恢复α-DG糖基化，但与fukutin共表达可强烈增强α-DG糖基化。总之，我们的数据表明，在α-DG糖基化的大剂量依赖性修复中，需要fukutin，从而为靶向肌纤维的大剂量治疗提供了新的方向。
α-Dystroglycanopathy (α-DGP) is a group of muscular dystrophy characterized by abnormal glycosylation of α-dystroglycan (α-DG), including Fukuyama congenital muscular dystrophy (FCMD), muscle-eye-brain disease, Walker-Warburg syndrome, and congenital muscular dystrophy type 1D (MDC1D), etc. LARGE, the causative gene for MDC1D, encodes a glycosyltransferase to form [-3Xyl-α1,3GlcAβ1-] polymer in the terminal end of the post-phosphoryl moiety, which is essential for α-DG function. It has been proposed that LARGE possesses the great potential to rescue glycosylation defects in α-DGPs regardless of causative genes. However, the in vivo therapeutic benefit of using LARGE activity is controversial. To explore the conditions needed for successful LARGE gene therapy, here we used Large-deficient and fukutin-deficient mouse models for MDC1D and FCMD, respectively. Myofibre-selective LARGE expression via systemic adeno-associated viral gene transfer ameliorated dystrophic pathology of Large-deficient mice even when intervention occurred after disease manifestation. However, the same strategy failed to ameliorate the dystrophic phenotype of fukutin-conditional knockout mice. Furthermore, forced expression of Large in fukutin-deficient embryonic stem cells also failed to recover α-DG glycosylation, however coexpression with fukutin strongly enhanced α-DG glycosylation. Together, our data demonstrated that fukutin is required for LARGE-dependent rescue of α-DG glycosylation, and thus suggesting new directions for LARGE-utilizing therapy targeted to myofibres.
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DOI：
10.1126/science.1233675
发表时间：
2013-04-26
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Jae LT;Raaben M;Riemersma M;van Beusekom E;Blomen VA;Velds A;Kerkhoven RM;Carette JE;Topaloglu H;Meinecke P;Wessels MW;Lefeber DJ;Whelan SP;van Bokhoven H;Brummelkamp TR
通讯作者：
Brummelkamp TR
影响因子：
4.8
作者：
Kanagawa, Motoi;Omori, Yoshihiro;Toda, Tatsushi
通讯作者：
Toda, Tatsushi
影响因子：
4.5
作者：
Lefeber DJ;de Brouwer AP;Morava E;Riemersma M;Schuurs-Hoeijmakers JH;Absmanner B;Verrijp K;van den Akker WM;Huijben K;Steenbergen G;van Reeuwijk J;Jozwiak A;Zucker N;Lorber A;Lammens M;Knopf C;van Bokhoven H;Grünewald S;Lehle L;Kapusta L;Mandel H;Wevers RA
通讯作者：
Wevers RA
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
9.8
作者：
Brockington, M;Blake, DJ;Muntoni, F
通讯作者：
Muntoni, F