Mannosidase I inhibition rescues the human α-sarcoglycan R77C recurrent mutation
Open Access
- 5 February 2008
- journal article
- research article
- Published by Oxford University Press (OUP) in Human Molecular Genetics
- Vol. 17 (9), 1214-1221
- https://doi.org/10.1093/hmg/ddn029
Abstract
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.This publication has 23 references indexed in Scilit:
- Molecular and cell biology of the sarcoglycan complexMuscle & Nerve, 2005
- The Dystrophin Glycoprotein ComplexCirculation Research, 2004
- The clinical spectrum of sarcoglycanopathiesNeurology, 1999
- Progressive Muscular Dystrophy in α-Sarcoglycan–deficient MiceThe Journal of cell biology, 1998
- Mutational diversity and hot spots in the alpha-sarcoglycan gene in autosomal recessive muscular dystrophy (LGMD2D).Journal of Medical Genetics, 1997
- Primary adhalinopathy (α‐sarcoglycanopathy)Neurology, 1997
- Autosomal recessive muscular dystrophy and mutations of the sarcoglycan complexNeuromuscular Disorders, 1996
- The sarcoglycan complex in the six autosomal recessive limb-girdle muscular dystrophiesHuman Molecular Genetics, 1996
- HyperCKemic, proximal muscular dystrophies and the dystrophin membrane cytoskeleton, including dystrophinopathies, sarcoglycanopathies, and merosinopathiesCurrent Opinion in Rheumatology, 1996
- Dystrophin and the membrane skeletonCurrent Opinion in Cell Biology, 1993