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Human Molecular Genetics Advance Access originally published online on February 5, 2008
Human Molecular Genetics 2008 17(9):1214-1221; doi:10.1093/hmg/ddn029
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Published by Oxford University Press 2008

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

Marc Bartoli1, Evelyne Gicquel1, Laetitia Barrault1, Tayebeh Soheili1, Marie Malissen2, Bernard Malissen2, Nathalie Vincent-Lacaze1, Norma Perez1, Bjarne Udd3, Olivier Danos1 and Isabelle Richard1,*

1 Généthon, CNRS-FRE3018, Evry 91000, France 2 Centre d'immunologie de Luminy, Université de la Méditerranée, Marseille 13009, France 3 Neurological Department, Vaasa Central Hospital, Finland

* To whom correspondence should be addressed at: Généthon, CNRS FRE3087, 1 bis rue de l'Internationale, 91000 Evry, France. Tel: +33 169472938; Fax: +33 160778698; Email: richard{at}genethon.fr

Received November 8, 2007; Revised January 18, 2008; Accepted January 25, 2008

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 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 {alpha}-sarcoglycan trafficking.


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