Mannosidase I inhibition rescues the human alpha-sarcoglycan R77C recurrent mutation.
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.
Bartoli
Marc
M
Généthon, CNRS-FRE3018, Evry 91000, France.
Gicquel
Evelyne
E
Barrault
Laetitia
L
Soheili
Tayebeh
T
Malissen
Marie
M
Malissen
Bernard
B
Vincent-Lacaze
Nathalie
N
Perez
Norma
N
Udd
Bjarne
B
Danos
Olivier
O
Richard
Isabelle
I
D000470:Alkaloids / Q000008:administration & dosage; D000818:Animals; D045744:Cell Line, Tumor; D003545:Cysteine / Q000235:genetics; D005260:Female; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D008361:Mannosidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009132:Muscles / Q000473:pathology / Q000821:virology; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics; D009137:Muscular Dystrophy, Animal / Q000378:metabolism / Q000821:virology; D020125:Mutation, Missense; D010641:Phenotype; D021381:Protein Transport / Q000187:drug effects; D049031:Sarcoglycans / Q000032:analysis / Q000235:genetics* / Q000378:metabolism*
D000470:Alkaloids; D007976:Leupeptins; D049031:Sarcoglycans; C065629:kifunensine; D008361:Mannosidases; C046090:mannosyl-oligosaccharide 1,2-alpha-mannosidase; D003545:Cysteine; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde