Journal article
A 5′ Dystrophin Duplication Mutation Causes Membrane Deficiency of α-Dystroglycan in a Family with X-linked Cardiomyopathy
Journal of molecular and cellular cardiology, Vol.29(12), pp.3175-3188
1997
DOI: 10.1006/jmcc.1997.0568
PMID: 9441825
Abstract
5′-mutations in the dystrophin gene can result in cardiomyopathy without clinically-apparent skeletal myopathy. The effect of dystrophin mutations on the assembly and stability of the dystrophin associated protein (DAP) complex in human heart are not fully understood. The molecular defect in the dystrophin complex was explored in a family with an X-linked pedigree and severe dilated cardiomyopathy. Dystrophin gene analysis demonstrated a 5′ duplication involving exons 2–7, which encodes the N-terminal actin binding domain of dystrophin. Ribonuclease protection and PCR assays demonstrated a reduction in muscle promoter transcribed dystrophin mRNA in the heart compared to skeletal muscle. A deficiency of cardiac dystrophin protein was observed by Western blot and lack of membrane localization by immunocytochemistry. The cardiac expression of the dystrophin related protein utrophin was increased, and the 43 kDa (
β-dystroglycan), 50 kDa (
α-sarcoglycan) and 59 kDa (syntrophin) dystrophin associated proteins (DAPs) were co-isolated and present in nearly normal amounts in the membrane. However, cardiac dystrophin deficiency and increased utrophin expression were associated with loss of extracellular 156 kDa dystrophin associated glycoprotein (
α-dystroglycan) binding to the cardiomyocyte membrane.
α-Dystroglycan is responsible for linkage of the dystrophin complex to the extracellular matrix protein laminin. Therefore, 5′ dystrophin mutations can reduce cardiac dystrophin mRNA, protein expression, and dystrophin function in X-linked cardiomyopathy (XLCM). The presence of membrane-associated
β-dystroglycan,
α-sarcoglycan, syntrophin, and utrophin are insufficient to maintain cardiac function. This XLCM family has a 5′ dystrophin gene mutation resulting in cardiac dystrophin deficiency and a loss of
α-dystroglycan membrane binding.
Details
- Title: Subtitle
- A 5′ Dystrophin Duplication Mutation Causes Membrane Deficiency of α-Dystroglycan in a Family with X-linked Cardiomyopathy
- Creators
- Roger D BiesMasato MaedaSteven L RoberdsEmma HolderTeresa BohlmeyerJames B YoungKevin P Campbell
- Resource Type
- Journal article
- Publication Details
- Journal of molecular and cellular cardiology, Vol.29(12), pp.3175-3188
- Publisher
- Elsevier Ltd
- DOI
- 10.1006/jmcc.1997.0568
- PMID
- 9441825
- ISSN
- 0022-2828
- eISSN
- 1095-8584
- Language
- English
- Date published
- 1997
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Iowa Neuroscience Institute
- Record Identifier
- 9984020712702771
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