Repairing folding-defective α-sarcoglycan mutants by CFTR correctors, a potential therapy for limb-girdle muscular dystrophy 2D

Hum Mol Genet. 2018 Mar 15;27(6):969-984. doi: 10.1093/hmg/ddy013.


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, we 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. Remarkably, in myotubes from a patient with LGMD2D, treatment with CFTR correctors induced the proper re-localization of the whole sarcoglycan complex, with a consequent reduction of sarcolemma fragility. Although the mechanism of action of CFTR correctors on defective α-sarcoglycan needs further investigation, this is the first report showing a quantitative and functional recovery of the sarcoglycan-complex in human pathologic samples, upon small molecule treatment. It represents the proof of principle of a pharmacological strategy that acts on the sarcoglycan maturation process and we believe it has a great potential to develop as a cure for most of the patients with LGMD2D.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cell Membrane / metabolism
  • Cystic Fibrosis Transmembrane Conductance Regulator / metabolism
  • HEK293 Cells
  • Humans
  • Muscle Contraction
  • Muscle, Skeletal / metabolism
  • Muscle, Striated / metabolism
  • Mutation, Missense
  • Proof of Concept Study
  • Sarcoglycanopathies / drug therapy*
  • Sarcoglycanopathies / genetics
  • Sarcoglycanopathies / metabolism
  • Sarcoglycans / genetics
  • Sarcoglycans / metabolism*


  • CFTR protein, human
  • SGCA protein, human
  • Sarcoglycans
  • Cystic Fibrosis Transmembrane Conductance Regulator