Human Molecular Genetics 2008-05-01

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

Marc Bartoli, Evelyne Gicquel, Laetitia Barrault, Tayebeh Soheili, Marie Malissen, Bernard Malissen, Nathalie Vincent-Lacaze, Norma Perez, Bjarne Udd, Olivier Danos, Isabelle Richard

文献索引：Hum. Mutat. 17 , 1214-21, (2008)

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摘要

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.