| First Author | Bartoli M | Year | 2008 |
| Journal | Hum Mol Genet | Volume | 17 |
| Issue | 9 | Pages | 1214-21 |
| PubMed ID | 18252745 | Mgi Jnum | J:133929 |
| Mgi Id | MGI:3784659 | Doi | 10.1093/hmg/ddn029 |
| Citation | Bartoli M, et al. (2008) Mannosidase I inhibition rescues the human alpha-sarcoglycan R77C recurrent mutation. Hum Mol Genet 17(9):1214-21 |
| abstractText | 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. |
