Résumé :
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Mutations in fukutin related protein (FKRP) are responsible for a common group of muscular dystrophies ranging from adult onset limb girdle muscular dystrophies to severe congenital forms with associated structural brain involvement, including Muscle Eye Brain Disease. A common feature of these disorders is a variable reduction in the glycosylation of skeletal muscle alpha-dystroglycan (ADG). Glycosylated ADG is an essential component of the dystrophin-related glycoprotein complex (DGC) whose known ECM ligands include laminin alpha 2, perlecan, agrin and neurexin. The glycans that decorate ADG mediate these interactions and their loss, specifically those identified by the antibody IIH6, are associated with a group of neuromuscular disorders now collectively known as the dystroglycanopathies. We have previously generated a mouse with a knock-down in Fkrp expression levels (FKRPKD) due to insertion of a floxed neomycin cassette in intron 2 of the mouse Fkrp gene. Since this mouse dies at birth due to central nervous involvement we have now replaced FKRP activity in the developing neural tube by crossing this line with one expressing Cre recombinase under the Sox-1 promoter. This has resulted in a near normal lifespan and a marked muscle phenotype by 12 weeks of age. This mouse should prove invaluable in the design and testing of future therapeutic strategies in the dystroglycanopathies.
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