title: Fukutin is prerequisite to ameliorate muscular dystrophic phenotype by myofiber-selective LARGE expression.
abstract: 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.
authors: Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, Kobe, 650-0017, Japan.
authors: Yoshihisa
authors: Y
authors: Ohtsuka
authors: Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, Kobe, 650-0017, Japan.
authors: Motoi
authors: M
authors: Kanagawa
authors: Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, Kobe, 650-0017, Japan.
authors: Chih-Chieh
authors: CC
authors: Yu
authors: Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, Kobe, 650-0017, Japan.
authors: Chiyomi
authors: C
authors: Ito
authors: Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, 187-8502, Japan.
authors: Tomoko
authors: T
authors: Chiyo
authors: Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, Kobe, 650-0017, Japan.
authors: Kazuhiro
authors: K
authors: Kobayashi
authors: Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, 187-8502, Japan.
authors: Takashi
authors: T
authors: Okada
authors: Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, 187-8502, Japan.
authors: Shin'ichi
authors: S
authors: Takeda
authors: Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, Kobe, 650-0017, Japan.
authors: Tatsushi
authors: T
authors: Toda
mesh_terms: D000818:Animals; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D049030:Dystroglycans / Q000378:metabolism; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D006031:Glycosylation; D051379:Mice; D018345:Mice, Knockout; D018485:Muscle Fibers, Skeletal / Q000378:metabolism* / Q000473:pathology; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics*; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D014161:Transduction, Genetic; D014166:Transferases; D058494:Walker-Warburg Syndrome / Q000235:genetics* / Q000378:metabolism / Q000628:therapy
chemical_list: D011506:Proteins; D049030:Dystroglycans; C491879:Fcmd protein, mouse; D014166:Transferases; D017351:N-Acetylglucosaminyltransferases