Mannosidase I inhibition rescues the human alpha-sarcoglycan R77C recurrent mutation

Hum Mol Genet. 2008 May 1;17(9):1214-21. doi: 10.1093/hmg/ddn029. Epub 2008 Feb 5.


Limb girdle muscular dystrophy type 2D (LGMD2D, OMIM600119) is a genetic progressive myopathy that is caused by mutations in the human alpha-sarcoglycan gene (SGCA). Here, we have introduced in mice the most prevalent LGMD2D mutation, R77C. It should be noted that the natural murine residue at this position is a histidine. The model is, therefore, referred as Sgca(H77C/H77C). Unexpectedly, we observed an absence of LGMD2D-like phenotype at histological or physiological level. Using a heterologous cellular model of the sarcoglycan complex formation, we showed that the R77C allele encodes a protein that fails to be delivered to its proper cellular localization in the plasma membrane, and consequently to the disappearance of a positively charged residue. Subsequently, we transferred an AAV vector coding for the human R77C protein in the muscle of Sgca-null mice and were able to pharmacologically rescue the R77C protein from endoplasmic reticulum-retention using proteasome or mannosidase I inhibitors. This suggests a therapeutic approach for LGMD2D patients carrying mutations that impair alpha-sarcoglycan trafficking.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkaloids / administration & dosage
  • Animals
  • Cell Line, Tumor
  • Cysteine / genetics
  • Female
  • Humans
  • Leupeptins / pharmacology
  • Mannosidases / antagonists & inhibitors
  • Mannosidases / metabolism*
  • Mice
  • Mice, Knockout
  • Muscles / pathology
  • Muscles / virology
  • Muscular Dystrophies, Limb-Girdle / genetics
  • Muscular Dystrophy, Animal / metabolism
  • Muscular Dystrophy, Animal / virology
  • Mutation, Missense*
  • Phenotype
  • Protein Transport / drug effects
  • Sarcoglycans / analysis
  • Sarcoglycans / genetics*
  • Sarcoglycans / metabolism*


  • Alkaloids
  • Leupeptins
  • Sarcoglycans
  • kifunensine
  • Mannosidases
  • mannosyl-oligosaccharide 1,2-alpha-mannosidase
  • Cysteine
  • benzyloxycarbonylleucyl-leucyl-leucine aldehyde