Journal article
A Common Disease-Associated Missense Mutation in Alpha-Sarcoglycan Fails to Cause Muscular Dystrophy in Mice
Human molecular genetics, Vol.17(9), pp.1201-1213
05/01/2008
DOI: 10.1093/hmg/ddn009
PMCID: PMC2713597
PMID: 18252746
Abstract
Limb-girdle muscular dystrophy type 2D (LGMD2D) is caused by autosomal recessive mutations in the α-sarcoglycan gene. An R77C substitution is the most prevalent cause of the disease, leading to disruption of the sarcoglycan-sarcospan complex. To model this common mutation, we generated knock-in mice with an H77C substitution in α-sarcoglycan. The floxed neomycin (Neo)-cassette retained at the targeted
H77C α-sarcoglycan
locus caused a loss of α-sarcoglycan expression, resulting in muscular dystrophy in homozygotes, whereas Cre-mediated deletion of the floxed Neo-cassette led to recovered H77C α-sarcoglycan expression. Contrary to expectations, mice homozygous for the H77C-encoding allele expressed both this mutant α-sarcoglycan and the other components of the sarcoglycan-sarcospan complex in striated muscle, and did not develop muscular dystrophy. Accordingly, conditional rescued expression of the H77C protein in striated muscle of the α-sarcoglycan-deficient mice prevented the disease. Adding to the case that the behavior of mutant α-sarcoglycan is different between humans and mice, mutant human R77C α-sarcoglycan restored the expression of the sarcoglycan-sarcospan complex when introduced by adenoviral vector into the skeletal muscle of previously created
α-sarcoglycan
null mice. These findings indicate that the α-sarcoglycan with the most frequent missense mutation in LGMD2D is correctly processed, is transported to the sarcolemma, and is fully functional in mouse muscle. Our study presents an unexpected difference in the behavior of a missense-mutated protein in mice versus human patients, and emphasizes the need to understand species-specific protein quality control systems.
Details
- Title: Subtitle
- A Common Disease-Associated Missense Mutation in Alpha-Sarcoglycan Fails to Cause Muscular Dystrophy in Mice
- Creators
- Kazuhiro Kobuke - Howard Hughes Medical Institute, Departments of Molecular Physiology and Biophysics, Neurology, and Internal Medicine, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa 52242, USAFederica Piccolo - Howard Hughes Medical Institute, Departments of Molecular Physiology and Biophysics, Neurology, and Internal Medicine, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa 52242, USAKeith W Garringer - University of Iowa, Molecular Physiology and BiophysicsSteven A Moore - University of Iowa, PathologyEileen Sweezer - Department of Obstetrics and Gynecology, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa 52242, USABaoli Yang - University of Iowa, BioVentures CenterKevin P Campbell - University of Iowa, Molecular Physiology and Biophysics
- Resource Type
- Journal article
- Publication Details
- Human molecular genetics, Vol.17(9), pp.1201-1213
- DOI
- 10.1093/hmg/ddn009
- PMID
- 18252746
- PMCID
- PMC2713597
- ISSN
- 0964-6906
- eISSN
- 1460-2083
- Language
- English
- Date published
- 05/01/2008
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Pathology; Iowa Neuroscience Institute; BioVentures Center; Obstetrics and Gynecology
- Record Identifier
- 9983557242302771
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