title: Adeno-associated virus-mediated overexpression of LARGE rescues α-dystroglycan function in dystrophic mice with mutations in the fukutin-related protein.
abstract: Multiple genes (e.g., POMT1, POMT2, POMGnT1, ISPD, GTDC2, B3GALNT2, FKTN, FKRP, and LARGE) are known to be involved in the glycosylation pathway of α-dystroglycan (α-DG). Mutations of these genes result in muscular dystrophies with wide phenotypic variability. Abnormal glycosylation of α-DG with decreased extracellular ligand binding activity is a common biochemical feature of these genetic diseases. While it is known that LARGE overexpression can compensate for defects in a few aforementioned genes, it is unclear whether it can also rescue defects in FKRP function. We examined adeno-associated virus (AAV)-mediated LARGE or FKRP overexpression in two dystrophic mouse models with loss-of-function mutations: (1) Large(myd) (LARGE gene) and (2) FKRP(P448L) (FKRP gene). The results agree with previous findings that overexpression of LARGE can ameliorate the dystrophic phenotypes of Large(myd) mice. In addition, LARGE overexpression in the FKRP(P448L) mice effectively generated functional glycosylation (hyperglycosylation) of α-DG and improved dystrophic pathologies in treated muscles. Conversely, FKRP transgene overexpression failed to rescue the defect in glycosylation and improve the phenotypes of the Large(myd) mice. Our findings suggest that AAV-mediated LARGE gene therapy may still be a viable therapeutic strategy for dystroglycanopathies with FKRP deficiency.
authors.affiliation: 1 McColl-Lockwood Laboratory for Muscular Dystrophy Research, Cannon Research Center, Carolinas Medical Center , Carolinas Healthcare System, Charlotte, NC 28231.
authors.forename: Charles H
authors.initials: CH
authors.lastname: Vannoy
authors.forename: Lei
authors.initials: L
authors.lastname: Xu
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Keramaris
authors.forename: Pei
authors.initials: P
authors.lastname: Lu
authors.forename: Xiao
authors.initials: X
authors.lastname: Xiao
authors.forename: Qi Long
authors.initials: QL
authors.lastname: Lu
mesh_terms: D000818:Animals; D002460:Cell Line; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D049030:Dystroglycans / Q000378:metabolism*; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009136:Muscular Dystrophies / Q000235:genetics / Q000473:pathology / Q000628:therapy; D009154:Mutation; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics / Q000378:metabolism*; D010430:Pentosyltransferases; D010641:Phenotype; D011506:Proteins / Q000235:genetics* / Q000378:metabolism*
chemical_list: D011506:Proteins; D049030:Dystroglycans; C117674:LARGE1 protein, human; D017351:N-Acetylglucosaminyltransferases; C443107:FKRP protein, human; D010430:Pentosyltransferases