Alternative titles; symbols
SNOMEDCT: 702424003; ORPHA: 154; DO: 0110461;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xp21.2-p21.1 | Cardiomyopathy, dilated, 3B | 302045 | X-linked | 3 | DMD | 300377 |
A number sign (#) is used with this entry because of evidence that X-linked dilated cardiomyopathy-3B (CMD3B) is caused by mutation in the gene encoding dystrophin (DMD; 300377) on chromosome Xp21.
X-linked dilated cardiomyopathy is a prominent feature of Barth syndrome (302060), caused by mutation in the TAZ gene (300394) on chromosome Xq28.
For a general phenotypic description and a discussion of genetic heterogeneity of dilated cardiomyopathy, see 115200.
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.
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).
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.
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.
Bastianutto, C., Bestard, J. A., Lahnakoski, K., Broere, D., De Visser, M., Zaccolo, M., Pozzan, T., Ferlini, A., Muntoni, F., Patarnello, T., Klamut, H. J. Dystrophin muscle enhancer 1 is implicated in the activation of non-muscle isoforms in the skeletal muscle of patients with X-linked dilated cardiomyopathy. Hum. Molec. Genet. 10: 2627-2635, 2001. [PubMed: 11726549] [Full Text: https://doi.org/10.1093/hmg/10.23.2627]
Berko, B. A., Swift, M. X-linked dilated cardiomyopathy. New Eng. J. Med. 316: 1186-1191, 1987. [PubMed: 3574369] [Full Text: https://doi.org/10.1056/NEJM198705073161904]
Biorck, G., Orinius, E. Familial cardiomyopathies. Acta Med. Scand. 176: 407-424, 1964. [PubMed: 14221653]
Csanady, M., Szasz, K. Familial cardiomyopathy. Cardiology 61: 122-130, 1976. [PubMed: 975127] [Full Text: https://doi.org/10.1159/000169753]
De Repentigny, Y., Marshall, P., Worton, R. G., Kothary, R. The mouse dystrophin muscle enhancer-1 imparts skeletal muscle, but not cardiac muscle, expression onto the dystrophin Purkinje promoter in transgenic mice. Hum. Molec. Genet. 13: 2853-2862, 2004. [PubMed: 15385445] [Full Text: https://doi.org/10.1093/hmg/ddh305]
Evans, W. Familial cardiomegaly. Brit. Heart J. 11: 68-82, 1949. [PubMed: 18113470] [Full Text: https://doi.org/10.1136/hrt.11.1.68]
Milasin, J., Muntoni, F., Severini, G. M., Bartoloni, L., Vatta, M., Krajinovic, M., Mateddu, A., Angelini, C., Camerini, F., Falaschi, A., Mestroni, L., Giacca, M., Heart Muscle Disease Study Group. A point mutation in the 5-prime splice site of the dystrophin gene first intron responsible for X-linked dilated cardiomyopathy. Hum. Molec. Genet. 5: 73-79, 1996. [PubMed: 8789442] [Full Text: https://doi.org/10.1093/hmg/5.1.73]
Muntoni, F., Cau, M., Ganau, A., Congiu, R., Arvedi, G., Mateddu, A., Marrosu, M. G., Cianchetti, C., Realdi, G., Cao, A., Melis, M. A. Deletion of the dystrophin muscle-promoter region associated with X-linked dilated cardiomyopathy. New Eng. J. Med. 329: 921-925, 1993. [PubMed: 8361506] [Full Text: https://doi.org/10.1056/NEJM199309233291304]
Ortiz-Lopez, R., Li, H., Su, J., Goytia, V., Towbin, J. A. Evidence for a dystrophin missense mutation as a cause of X-linked dilated cardiomyopathy. Circulation 95: 2434-2440, 1997. [PubMed: 9170407] [Full Text: https://doi.org/10.1161/01.cir.95.10.2434]
Ross, R. S., Bulkley, B. H., Hutchins, G. M., Harshey, J. S., Jones, R. A., Kraus, H., Liebman, J., Thorne, C. M., Weinberg, S. B., Weech, A. A., Weech, A. A., Jr. Idiopathic familial cardiomyopathy in three generations: a clinical and pathologic study. Am. Heart J. 96: 170-179, 1978. [PubMed: 676978] [Full Text: https://doi.org/10.1016/0002-8703(78)90082-0]
Taylor, M. R. G., Ku, L., Slavov, D., Cavanaugh, J., Boucek, M., Zhu, X., Graw, S., Carniel, E., Barnes, C., Quan, D., Prall, R., Lovell, M. A., Mierau, G., Ruegg, P., Mandava, N., Bristow, M. R., Towbin, J. A., Mestroni, L. Danon disease presenting with dilated cardiomyopathy and a complex phenotype. J. Hum. Genet. 52: 830-835, 2007. [PubMed: 17899313] [Full Text: https://doi.org/10.1007/s10038-007-0184-8]
Towbin, J. A., Hejtmancik, J. F., Brink, P., Gelb, B., Zhu, X. M., Chamberlain, J. S., McCabe, E. R. B., Swift, M. X-linked dilated cardiomyopathy: molecular genetic evidence of linkage to the Duchenne muscular dystrophy (dystrophin) gene at the Xp21 locus. Circulation 87: 1854-1865, 1993. [PubMed: 8504498] [Full Text: https://doi.org/10.1161/01.cir.87.6.1854]
Towbin, J. A., Zhu, X. M., Gelb, B., Bies, R., Chamberlain, J., Maichele, A., Ohlendieck, K., Campbell, K., McCabe, E. R. B., Swift, M. X-linked dilated cardiomyopathy (XLCM): molecular characterization. (Abstract) Am. J. Hum. Genet. 49 (suppl.): 421 only, 1991.