Rescue of sarcoglycan mutations by inhibition of endoplasmic reticulum quality control is associated with minimal structural modifications
- 16 November 2011
- journal article
- research article
- Published by Hindawi Limited in Human Mutation
- Vol. 33 (2), 429-439
- https://doi.org/10.1002/humu.21659
Abstract
Sarcoglycanopathies (SGP) are a group of autosomal recessive muscle disorders caused by primary mutations in one of the four sarcoglycan genes. The sarcoglycans (α-, β-, γ-, and δ-sarcoglycan) form a tetrameric complex at the muscle membrane that is part of the dystrophin-glycoprotein complex and plays an essential role for membrane integrity during muscle contractions. We previously showed that the most frequent missense mutation in α-sarcoglycan (p.R77C) leads to the absence of the protein at the cell membrane due to its blockade by the endoplasmic reticulum (ER) quality control. Moreover, we demonstrated that inhibition of the ER α-mannosidase I activity using kifunensine could rescue the mutant protein localization at the cell membrane. Here, we investigate 25 additional disease-causing missense mutations in the sarcoglycan genes with respect to intracellular fate and localization rescue of the mutated proteins by kifunensine. Our studies demonstrate that, similarly to p.R77C, 22 of 25 of the selected mutations lead to defective intracellular trafficking of the SGs proteins. Six of these were saved from ER retention upon kifunensine treatment. The trafficking of SGs mutants rescued by kifunensine was associated with mutations that have moderate structural impact on the protein. Hum Mutat 33:429–439, 2012.This publication has 48 references indexed in Scilit:
- Sarcoglycanopathies: molecular pathogenesis and therapeutic prospectsExpert Reviews in Molecular Medicine, 2009
- Spectrum of mutations in sarcoglycan genes in the Mumbai region of western India: High prevalence of 525del TNeurology India, 2009
- Inhibition of Proteasome Activity Promotes the Correct Localization of Disease-Causing α-Sarcoglycan Mutants in HEK-293 Cells Constitutively Expressing β-, γ-, and δ-SarcoglycanThe American Journal of Pathology, 2008
- A common disease-associated missense mutation in alpha-sarcoglycan fails to cause muscular dystrophy in miceHuman Molecular Genetics, 2008
- Mannosidase I inhibition rescues the human α-sarcoglycan R77C recurrent mutationHuman Molecular Genetics, 2008
- Identification of functional domains in sarcoglycans essential for their interaction and plasma membrane targetingExperimental Cell Research, 2006
- Specific assembly pathway of sarcoglycans is dependent on beta‐ and delta‐sarcoglycanMuscle & Nerve, 2004
- Cadherin-like domains in α-dystroglycan, α/ε-sarcoglycan and yeast and bacterial proteinsCurrent Biology, 2002
- Two types of amino acid substitutions in protein evolutionJournal of Molecular Evolution, 1979
- Amino Acid Difference Formula to Help Explain Protein EvolutionScience, 1974