Journal Article

Mannosidase I inhibition rescues the human α-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 and Isabelle Richard

in Human Molecular Genetics

Volume 17, issue 9, pages 1214-1221
Published in print May 2008 | ISSN: 0964-6906
Published online February 2008 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddn029
Mannosidase I inhibition rescues the human α-sarcoglycan R77C recurrent mutation

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Limb girdle muscular dystrophy type 2D (LGMD2D, OMIM600119) is a genetic progressive myopathy that is caused by mutations in the human α-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 SgcaH77C/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 α-sarcoglycan trafficking.

Journal Article.  5250 words.  Illustrated.

Subjects: Genetics and Genomics

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