90002671

open access

Version of Record

Contribution of Dysferlin Deficiency to Skeletal Muscle Pathology in Asymptomatic and Severe Dystroglycanopathy Models:Generation of a New Model for Fukuyama Congenital Muscular Dystrophy

English (英語)

PLoS ONE

9(9)

e106721-e106721

Public Library of Science

2014-09

2015-02-19

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 dysferlinˢʲˡ/ˢʲˡ mice to the fukutin-knock-in fukutinᴴᵖ/⁻ and Large-deficient Largeᵐʸᵈ/ᵐʸᵈ mice, which are phenotypically distinct models of dystroglycanopathy. The fukutinᴴᵖ/⁻ mice do not show a dystrophic phenotype; however, (dysferlinˢʲˡ/ˢʲˡ: fukutinᴴᵖ/⁻) mice showed a deteriorated phenotype compared with (dysferlinˢʲˡ/ˢʲˡ: fukutinᴴᵖ/⁺) mice. These data indicate that the absence of functional dysferlin in the asymptomatic fukutinᴴᵖ/⁻ 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 fukutinᴴᵖ/⁻ FCMD mouse model, and the (dysferlinˢʲˡ/ˢʲˡ: fukutinᴴᵖ/⁻) mice will be useful as a novel model for a recently proposed antisense oligonucleotide therapy for FCMD.

学術雑誌論文