title: Contribution of dysferlin deficiency to skeletal muscle pathology in asymptomatic and severe dystroglycanopathy models: generation of a new model for Fukuyama congenital muscular dystrophy.
abstract: Defects in dystroglycan glycosylation are associated with a group of muscular dystrophies, termed dystroglycanopathies, that include Fukuyama congenital muscular dystrophy (FCMD). It is widely believed that abnormal glycosylation of dystroglycan leads to disease-causing membrane fragility. We previously generated knock-in mice carrying a founder retrotransposal insertion in fukutin, the gene responsible for FCMD, but these mice did not develop muscular dystrophy, which hindered exploring therapeutic strategies. We hypothesized that dysferlin functions may contribute to muscle cell viability in the knock-in mice; however, pathological interactions between glycosylation abnormalities and dysferlin defects remain unexplored. To investigate contributions of dysferlin deficiency to the pathology of dystroglycanopathy, we have crossed dysferlin-deficient dysferlin(sjl/sjl) mice to the fukutin-knock-in fukutin(Hp/-) and Large-deficient Largemyd/myd mice, which are phenotypically distinct models of dystroglycanopathy. The fukutin(Hp/-) mice do not show a dystrophic phenotype; however, (dysferlin(sjl/sjl): fukutin(Hp/-)) mice showed a deteriorated phenotype compared with (dysferlinsjl/sjl: fukutin(Hp/+)) mice. These data indicate that the absence of functional dysferlin in the asymptomatic fukutin(Hp/-) mice triggers disease manifestation and aggravates the dystrophic phenotype. A series of pathological analyses using double mutant mice for Large and dysferlin indicate that the protective effects of dysferlin appear diminished when the dystrophic pathology is severe and also may depend on the amount of dysferlin proteins. Together, our results show that dysferlin exerts protective effects on the fukutin(Hp/-) FCMD mouse model, and the (dysferlin(sjl/sjl): fukutin(Hp/-)) mice will be useful as a novel model for a recently proposed antisense oligonucleotide therapy for FCMD.
authors.affiliation: Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Motoi
authors.initials: M
authors.lastname: Kanagawa
authors.affiliation: Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Zhongpeng
authors.initials: Z
authors.lastname: Lu
authors.affiliation: Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Chiyomi
authors.initials: C
authors.lastname: Ito
authors.affiliation: Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology, Tsukuba, Japan.
authors.forename: Chie
authors.initials: C
authors.lastname: Matsuda
authors.affiliation: Department of Histology and Cell Biology, School of Medicine, Kagawa University, Ikenobe, Miki, Kagawa, Japan.
authors.forename: Katsuya
authors.initials: K
authors.lastname: Miyake
authors.affiliation: Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Tatsushi
authors.initials: T
authors.lastname: Toda
mesh_terms: D000818:Animals; D000073939:Dysferlin; D049030:Dystroglycans / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009124:Muscle Proteins / Q000235:genetics*; D018482:Muscle, Skeletal / Q000473:pathology*; D058494:Walker-Warburg Syndrome / Q000235:genetics* / Q000378:metabolism
chemical_list: C114839:DYSF protein, human; D000073939:Dysferlin; D008565:Membrane Proteins; D009124:Muscle Proteins; D049030:Dystroglycans