A 5′ dystrophin duplication mutation causes membrane deficiency of α-dystroglycan in a family with X-linked cardiomyopathy

被引:40
作者
Bies, RD
Maeda, M
Roberds, SL
Holder, E
Bohlmeyer, T
Young, JB
Campbell, KP
机构
[1] Vet Adm Med Ctr, Div Cardiol, Denver, CO 80262 USA
[2] Univ Colorado, Hlth Sci Ctr, Denver, CO 80262 USA
[3] Univ Iowa, Coll Med, Howard Hughes Med Inst, Iowa City, IA 52242 USA
[4] Univ Iowa, Coll Med, Dept Physiol & Biophys, Iowa City, IA 52242 USA
[5] Cleveland Clin, Heart Failure & Transplant Div, Cleveland, OH 44195 USA
关键词
dystrophin; utrophin; alpha-dystroglycan; cardiomyopathy; muscular dystrophy;
D O I
10.1006/jmcc.1997.0568
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 (beta-dystroglycan), 50 kDa (alpha-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 (alpha-dystroglycan) binding to the cardiomyocyte membrane. alpha-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 beta-dystroglycan, alpha-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 alpha-dystroglycan membrane binding, (C) 1997 Academic Press Limited.
引用
收藏
页码:3175 / 3188
页数:14
相关论文
共 44 条
[1]   HUMAN AND MURINE DYSTROPHIN MESSENGER-RNA TRANSCRIPTS ARE DIFFERENTIALLY EXPRESSED DURING SKELETAL-MUSCLE, HEART, AND BRAIN-DEVELOPMENT [J].
BIES, RD ;
PHELPS, SF ;
CORTEZ, MD ;
ROBERTS, R ;
CASKEY, CT ;
CHAMBERLAIN, JS .
NUCLEIC ACIDS RESEARCH, 1992, 20 (07) :1725-1731
[2]   AN INTACT CYSTEINE-RICH DOMAIN IS REQUIRED FOR DYSTROPHIN FUNCTION [J].
BIES, RD ;
CASKEY, CT ;
FENWICK, R .
JOURNAL OF CLINICAL INVESTIGATION, 1992, 90 (02) :666-672
[3]   EXPRESSION AND LOCALIZATION OF DYSTROPHIN IN HUMAN CARDIAC PURKINJE-FIBERS [J].
BIES, RD ;
FRIEDMAN, D ;
ROBERTS, R ;
PERRYMAN, MB ;
CASKEY, CT .
CIRCULATION, 1992, 86 (01) :147-153
[4]   BETA-SARCOGLYCAN (A3B) MUTATIONS CAUSE AUTOSOMAL RECESSIVE MUSCULAR-DYSTROPHY WITH LOSS OF THE SARCOGLYCAN COMPLEX [J].
BONNEMANN, CG ;
MODI, R ;
NOGUCHI, S ;
MIZUNO, Y ;
YOSHIDA, M ;
GUSSONI, E ;
MCNALLY, EM ;
DUGGAN, DJ ;
ANGELINI, C ;
HOFFMAN, EP ;
OZAWA, E ;
KUNKEL, LM .
NATURE GENETICS, 1995, 11 (03) :266-273
[5]  
CHIRGWIN JM, 1979, BIOCHEMISTRY-US, V13, P2633
[6]   MEMBRANE ORGANIZATION OF THE DYSTROPHIN-GLYCOPROTEIN COMPLEX [J].
ERVASTI, JM ;
CAMPBELL, KP .
CELL, 1991, 66 (06) :1121-1131
[7]   ALTERNATIVE SPLICING OF HUMAN DYSTROPHIN MESSENGER-RNA GENERATES ISOFORMS AT THE CARBOXY TERMINUS [J].
FEENER, CA ;
KOENIG, M ;
KUNKEL, LM .
NATURE, 1989, 338 (6215) :509-511
[8]   X-LINKED DILATED CARDIOMYOPATHY NOVEL MUTATION OF THE DYSTROPHIN GENE [J].
FRANZ, WM ;
CREMER, M ;
HERRMANN, R ;
GRUNIG, E ;
FOGEL, W ;
SCHEFFOLD, T ;
GOEBEL, HH ;
KIRCHEISEN, R ;
KUBLER, W ;
VOIT, T ;
KATUS, HA .
CARDIAC GROWTH AND REGENERATION, 1995, 752 :470-491
[9]  
GOLDSTEIN J, 1988, HEART DIS, P1633
[10]   EXPRESSION OF 4 ALTERNATIVE DYSTROPHIN TRANSCRIPTS IN BRAIN-REGIONS REGULATED BY DIFFERENT PROMOTERS [J].
GORECKI, DC ;
MONACO, AP ;
DERRY, JMJ ;
WALKER, AP ;
BARNARD, EA ;
BARNARD, PJ .
HUMAN MOLECULAR GENETICS, 1992, 1 (07) :505-510