Quantitative and functional recovery of the sarcoglycan-complex in LGMD2D


Limb Girdle Muscular Dystrophy type 2D (LGMD2D) is a rare autosomal-recessive disease, affecting striated muscle, due to mutation of SGCA, the gene coding for α-sarcoglycan. Nowadays more than 50 different SGCA missense mutations have been reported. They are supposed to impact folding and trafficking of α-sarcoglycan because the defective polypeptide, although potentially functional, is recognized and disposed of by the quality control of the cell. The secondary reduction of α-sarcoglycan partners, β-, γ- and δ-sarcoglycan, disrupts a key membrane complex that, associated to dystrophin, contributes to assure sarcolemma stability during muscle contraction. The complex deficiency is responsible for muscle wasting and the development of a severe form of dystrophy. Here, the authors show that the application of small molecules developed to rescue ΔF508-CFTR trafficking, and known as CFTR correctors, also improved the maturation of several α-sarcoglycan mutants that were consequently rescued at the plasma membrane.

Carotti M, Marsolier J, Soardi M, et al. Repairing folding-defective α-sarcoglycan mutants by CFTR correctors, a potential therapy for Limb Girdle Muscular Dystrophy 2D. Hum Mol Genet. 2018 Jan 16. doi: 10.1093/hmg/ddy013. [Epub ahead of print]