Minimal Consequences of CMAH and DBA/2J Background on a FKRP Deficient Model

International audienceBackground: Muscular dystrophies (MD) are a large group of genetic diseases characterized by a progressive loss of muscle. The Latent TGFβ Binding Protein 4 (LTBP4) and the Cytidine Monophosphate-sialic Acid Hydroxylase (CMAH) proteins were previously identified as genetic modifiers in severe MD.Objective: We investigated whether these modifiers could also influence a mild phenotype such as the one observed in a mouse model of Limb-Girdle MD2I (LGMD2I).Methods: A polymorphism of LTBP4 leading to its reduced activity was introduced in a FKRP L276I mouse model using backcrossing onto the DBA/2 background whereas the Cmah gene was inactivated in FKRP L276I mice by crossing with a Cmah-/mouse and selecting the double-mutants. The mdx mouse was used as control for these 2 genome modifications. Consequences at the histological level as well as quantification of expression level by RT-qPCR of genes relevant for muscular dystrophy were then performed.Results: We showed that the reduced activity of LTBP4 has no observable effect on FKRP L276I mouse phenotype while drastically increases the level of inflammation and fibrosis in the mdx mouse as previously shown. The Cmah-/background has no effect on the FKRP L276I mouse phenotype and mostly leads to an increase of regeneration in the mdx mice.Conclusions: None of these modifiers impacted the severity of the presentation in the FKRP L276I model but an interesting association of the CMAH modifier with the regeneration process in the mdx model is shedding a new light on the influence of this protein on the dystrophic phenotype