DO: 0110318; MONDO: 0012804;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 11p15.1 | Cardiomyopathy, hypertrophic, 12 | 612124 | Autosomal dominant | 3 | CSRP3 | 600824 |
A number sign (#) is used with this entry because of evidence that familial hypertrophic cardiomyopathy-12 (CMH12) is caused by heterozygous mutation in the CSRP3 gene (600824) on chromosome 11p15.
For a phenotypic description and a discussion of genetic heterogeneity of familial hypertrophic cardiomyopathy, see CMH1 (192600).
Geier et al. (2008) reported the clinical characteristics of affected individuals from 5 CMH families with mutations in the CSRP3 gene, 3 of which had been previously studied by Geier et al. (2003). Most affected persons had pronounced hypertrophy and reported onset of symptoms in young adulthood. A history of sudden death was present in 2 families. Geier et al. (2008) observed considerable interindividual variability in the extent and localization of left ventricular hypertrophy: while most individuals with marked hypertrophy had asymmetric septal hypertrophy, 1 affected relative had severe apical hypertrophy, another had concentric, and another midventricular hypertrophy VSports app下载. Myocardial biopsy from the proband of a large German family previously studied by Geier et al. (2003) showed a histologic pattern typical for CMH, e. g. , variably hypertrophied cardiomyocytes, myocyte disarray, and perivascular and interstitial fibrosis and scarring. Electron microscopy displayed typical nuclear pleomorphism with bizarre lobulated cardiomyocyte nuclei and no gross abnormalities of the sarcomere. Immunohistochemistry of a biopsy sample from this patient revealed areas of inhomogeneous and patchy muscle LIM protein (MLP) staining. .
Skeletal Muscle Involvement
Because MLP is expressed in both myocardium and in slow-twitch skeletal muscle, Geier et al V体育官网. (2008) studied 5 CMH patients with CSRP3 mutations for skeletal muscle involvement. Three of the 5 patients complained of exertional myalgias and cramps and had moderately elevated creatine kinase levels. Skeletal muscle biopsies from the quadriceps or deltoid of 2 of the patients showed mild myopathic changes with cytoplasmic accumulation of amorphous material in a few fibers, changes considered typical for myofibrillar myopathy. .
Geier et al. (2008) examined 51 more members of a large German family with CMH, originally reported by Geier et al. (2003) and found to carry a heterozygous C58G mutation in the CSRP3 gene (600824.0002), and identified 5 additional affected individuals. Microsatellite analysis in the extended family excluded linkage to any known CMH loci and revealed a 5.5-cM interval between markers D11S1981 and D11S1755 as the only linkage support interval (maximum multipoint lod score of 5.9, theta = 0, reduced penetrance of 0.9); the critical interval comprised the CSRP3 locus on chromosome 11p15.1. Inclusion of 2 additional families found to carry mutations in CSRP3 by Geier et al. (2003) (see 600824.0003 and 600824.0004) in the haplotype analysis by Geier et al. (2008) confirmed segregation of the phenotype with markers at the CSRP3 locus.
Geier et al. (2003) analyzed the CSRP3 gene in 200 patients with hypertrophic cardiomyopathy (CMH), 400 patients with dilated cardiomyopathy (CMD), and 500 controls, and identified 3 different mutations (600824.0002-600824.0004) that cosegregated with CMH in 3 unrelated families. All known CMH disease genes were excluded in the largest family; no mutations were detected in the CMD patients or controls. The authors stated that all 3 probands had typical asymmetric septal hypertrophy; mutation-positive relatives in these families had mild symptoms and great variation in the extent of hypertrophy, although there was a history of sudden cardiac death in 2 of the 3 families.
Geier et al. (2008) sequenced exons 2 and 3 of the CSRP3 gene in 652 CMD and 354 CMH patients and 533 unrelated controls and identified heterozygosity for a missense mutation in CSRP3 in 2 unrelated CMH probands (600824.0006).
Geier, C., Gehmlich, K., Ehler, E., Hassfeld, S., Perrot, A., Hayess, K., Cardim, N., Wenzel, K., Erdmann, B., Krackhardt, F., Posch, M. G., Osterziel, K. J., and 9 others. Beyond the sarcomere: CSRP3 mutations cause hypertrophic cardiomyopathy. Hum. Molec. Genet. 17: 2753-2765, 2008. Note: Erratum: Hum. Molec. Genet. 17: 3436 only, 2008. [PubMed: 18505755] [Full Text: https://doi.org/10.1093/hmg/ddn160]
Geier, C., Perrot, A., Ozcelik, C., Binner, P., Counsell, D., Hoffmann, K., Pilz, B., Martiniak, Y., Gehmlich, K., van der Ven, P. F. M., Furst, D. O., Vornwald, A., von Hodenberg, E., Nurnberg, P., Scheffold, T., Dietz, R., Osterziel, K. J. Mutations in the human muscle LIM protein gene in families with hypertrophic cardiomyopathy. Circulation 107: 1390-1395, 2003. [PubMed: 12642359] [Full Text: https://doi.org/10.1161/01.cir.0000056522.82563.5f]