#302045
ICD+
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| CARDIOMYOPATHY, DILATED, 3B; CMD3B | |||||||||||||||||||||||||||||||||||||||
| Alternative titles; symbols | |||||||||||||||||||||||||||||||||||||||
| CARDIOMYOPATHY, DILATED, X-LINKED; XLCM | |||||||||||||||||||||||||||||||||||||||
| Phenotype Gene Relationships | |||||||||||||||||||||||||||||||||||||||
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| Phenotypic Series | |||||||||||||||||||||||||||||||||||||||
| Clinical Synopsis | |||||||||||||||||||||||||||||||||||||||
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| A number sign (#) is used with this entry because of evidence that one form of X-linked dilated cardiomyopathy is caused by in the gene encoding dystrophin (DMD; 300377). For a discussion of genetic heterogeneity of X-linked dilated cardiomyopathy, see CMD3A (300069). | |||||||||||||||||||||||||||||||||||||||
| Clinical Features | |||||||||||||||||||||||||||||||||||||||
| Berko and Swift (1987) described a black family in which 11 young male members had definite or possible evidence of dilated cardiomyopathy. The 5 affected males for whom they had complete clinical data survived for 5 to 12 months after the onset of symptoms, which occurred between ages 15 and 21 years. A diagnosis of definite late-onset dilated cardiomyopathy was given in 3 mothers of affected males and possible diagnosis was given in 2 others. These women presented in their forties with atypical chest pain, and progressive congestive heart failure developed gradually over a period of 10 or more years. Berko and Swift (1987) suggested that the affected males were hemizygous and the affected females heterozygous for a gene for idiopathic dilated cardiomyopathy. They pointed to a similar pedigree pattern in the families reported by Evans (1949), Biorck and Orinius (1964), Csanady and Szasz (1976), and Ross et al. (1978). Using antidystrophin antibody prepared to the N-terminal portion of dystrophin, Towbin et al. (1991) found low abundance cardiac dystrophin but normal skeletal muscle dystrophin in patients with XLCM. | |||||||||||||||||||||||||||||||||||||||
| Mapping | |||||||||||||||||||||||||||||||||||||||
| Towbin et al. (1993) did linkage studies in the large kindred reported by Berko and Swift (1987) and in a smaller new pedigree. Linkage of XLCM to the centromeric portion of the dystrophin locus was demonstrated, with combined maximum lod of 4.33 at theta = 0.0 using 2-point linkage and 4.81 using multipoint linkage analysis. No deletions were observed. Abnormalities of cardiac dystrophin were shown by Western blotting with N-terminal dystrophin antibody, whereas skeletal muscle dystrophin was normal, suggesting primary involvement of the DMD gene with cardiac muscle preferentially affected. Subsequently, in the smaller pedigree ('XLCM-2'), Taylor et al. (2007) identified a mutation in the LAMP2 gene (309060.0012), confirming a diagnosis of Danon disease (300257). | |||||||||||||||||||||||||||||||||||||||
| Molecular Genetics | |||||||||||||||||||||||||||||||||||||||
| Muntoni et al. (1993) demonstrated that an X-linked form of dilated cardiomyopathy was due to deletion in the promoter region and first exon of the DMD gene (300377.0021). Milasin et al. (1996) reported an XLCM family with a point mutation in the 5-prime splice site of the dystrophin E1-I1 boundary (300377.0025), and Ortiz-Lopez et al. (1997) found a causative mutation in exon 9 of the DMD gene (300377.0073) in a large North American kindred originally described by Berko and Swift (1987). Bastianutto et al. (2001) determined that 2 XLCM patients bore deletions that removed the muscle promoter and exon 1, but not the brain and cerebellar Purkinje promoters. The brain and cerebellar Purkinje promoters were found to be essentially inactive in muscle cell lines and primary cultures. Since dystrophin muscle enhancer-1 (DME1), a muscle-specific enhancer, is preserved in these patients, the authors tested its ability to upregulate the brain and cerebellar Purkinje promoters in muscle cells. Brain and cerebellar Purkinje (CP) promoter activity was significantly increased in the presence of DME1, and activation was observed exclusively in cells presenting a skeletal muscle phenotype versus cardiomyocytes. Bastianutto et al. (2001) suggested a role for DME1 in the induction of brain and cerebellar Purkinje isoform expression in the skeletal muscle of XLCM patients defective for muscle isoform expression. | |||||||||||||||||||||||||||||||||||||||
| Animal Model | |||||||||||||||||||||||||||||||||||||||
| De Repentigny et al. (2004) demonstrated that the mouse dystrophin CP promoter drove expression of a reporter gene specifically to the cerebellar Purkinje cell layer, but not to skeletal or cardiac muscle of transgenic mice. When the mouse counterpart of DME1 was present in the transgene construct, the dystrophin CP promoter was activated in skeletal muscle, but not in cardiac muscle. | |||||||||||||||||||||||||||||||||||||||
| REFERENCES | |||||||||||||||||||||||||||||||||||||||
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