DO: 0110319;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 3p21.1 | Cardiomyopathy, hypertrophic, 13 | 613243 | Autosomal dominant | 3 | TNNC1 | 191040 |
A number sign (#) is used with this entry because familial hypertrophic cardiomyopathy-13 (CMH13) is caused by heterozygous mutation in the TNNC1 gene (191040) on chromosome 3p21.
For a phenotypic description and a discussion of genetic heterogeneity of familial hypertrophic cardiomyopathy, see 192600.
Parvatiyar et al. (2012) studied a 5-year-old boy who at 3.75 years of age survived an episode of ventricular fibrillation, then underwent implantation of an intracardioverter defibrillator (ICD) and was maintained on beta-blockers. He subsequently had 5 episodes of breakthrough ventricular fibrillation, generally when emotionally excited and physically active, with a single ICD shock restoring normal sinus rhythm in each case. Echocardiography showed asymmetric septal wall hypertrophy with a mean left ventricular wall thickness of 20 mm (normal, 6-8 mm) with reverse curve morphology, ejection fraction of 65%, diastolic dysfunction, with no left ventricular outflow obstruction. He had moderate left atrial enlargement, and ECG demonstrated significant voltage criteria for biventricular hypertrophy, ST segment depression in anterior leads, and borderline QT prolongation with a QTc of 460 ms. Family history was negative for CMH or sudden cardiac death, and both parents were negative for CMH by echocardiography.
In a 60-year-old German man who presented with dyspnea on exertion and was found to have concentric hypertrophic cardiomyopathy (CMH) of the left ventricle, with 15-mm thick septal and posterior walls, Hoffmann et al. (2001) identified a heterozygous mutation in the TNNC1 gene (L29Q; 191040.0002). No family members were available for study. The mutation was not found in 96 controls, but the authors stated that they could not determine whether this was a disease-causing variant. Schmidtmann et al. (2005) studied the structural and functional consequences of the L29Q substitution and demonstrated alteration of the dynamics of the actin-myosin interaction as well as impairment of PKA (see 601639)-dependent signaling from cardiac TnI (191044) to cardiac TnC, resulting in an increased sensitivity to Ca(2+) when cardiac TnI is phosphorylated.
In 108 consecutive CMH patients diagnosed by echocardiography, angiography, or findings after myectomy, Erdmann et al. (2003) screened for mutations in 6 sarcomeric genes, but did not identify any disease-causing mutations in the TNNC1 gene.
Landstrom et al. (2008) analyzed the TNNC1 gene in 1,025 unrelated patients who met the clinical criteria for CMH, with maximum left ventricular wall thickness of greater than 13 mm in the absence of other confounding diagnoses, and identified 4 heterozygous missense mutations in 4 Caucasian patients (see, e.g., 191040.0003-191040.0005) who were negative for mutation in 15 known CMH-susceptibility genes. The mutations were not found in 400 Caucasian or 100 African American controls with normal screening ECGs and echocardiograms. Landstrom et al. (2008) noted that the prevalence of TNNC1 mutations in their cohort was approximately 0.4%, comparable in frequency to those previously reported by Van Driest et al. (2003) for both alpha-tropomyosin (CMH3; 115196) and actin (CMH11; 612098) mutations in a cohort of 388 CMH patients.
In a 5-year-old boy with CMH and a history of ventricular fibrillation, Parvatiyar et al. (2012) analyzed 12 CMH-associated genes and identified heterozygosity for a missense mutation in the TNNC1 gene (A31S; 191040.0006). Functional analysis suggested that the A31S mutation has a direct effect on the Ca(2+) sensitivity of the myofilament, which may alter Ca(2+) handling and contribute to the arrhythmogenesis observed in the proband.
Erdmann, J., Daehmlow, S., Wischke, S., Senyuva, M., Werner, U., Raible, J., Tanis, N., Dyachenko, S., Hummel, M., Hetzer, R., Regitz-Zagrosek, V. Mutation spectrum in a large cohort of unrelated consecutive patients with hypertrophic cardiomyopathy. Clin. Genet. 64: 339-349, 2003. [PubMed: 12974739] [Full Text: https://doi.org/10.1034/j.1399-0004.2003.00151.x]
Hoffmann, B., Schmidt-Traub, H., Perrot, A., Osterziel, K. J., Gessner, R. First mutation in cardiac troponin C, L29Q, in a patient with hypertrophic cardiomyopathy. Hum. Mutat. 17: 524 only, 2001. [PubMed: 11385718] [Full Text: https://doi.org/10.1002/humu.1143]
Landstrom, A. P., Parvatiyar, M. S., Pinto, J. R., Marquardt, M. L., Bos, J. M., Tester, D. J., Ommen, S. R., Potter, J. D., Ackerman, M. J. Molecular and functional characterization of novel hypertrophic cardiomyopathy susceptibility mutations in TNNC1-encoded troponin C. J. Molec. Cell. Cardiol. 45: 281-288, 2008. [PubMed: 18572189] [Full Text: https://doi.org/10.1016/j.yjmcc.2008.05.003]
Parvatiyar, M. S., Landstrom, A. P., Figueiredo-Freitas, C., Potter, J. D., Ackerman, M. J., Pinto, J. R. A mutation in TNNC1-encoded cardiac troponin C, TNNC1-A31S, predisposes to hypertrophic cardiomyopathy and ventricular fibrillation. J. Biol. Chem. 287: 31845-31855, 2012. [PubMed: 22815480] [Full Text: https://doi.org/10.1074/jbc.M112.377713]
Schmidtmann, A., Lindow, C., Villard, S., Heuser, A., Mugge, A., Gessner, R., Granier, C., Jaquet, K. Cardiac troponin C-L29Q, related to hypertrophic cardiomyopathy, hinders the transduction of the protein kinase A dependent phosphorylation signal from cardiac troponin I to C. FEBS J. 272: 6087-6097, 2005. [PubMed: 16302972] [Full Text: https://doi.org/10.1111/j.1742-4658.2005.05001.x]
Van Driest, S. L., Ellsworth, E. G., Ommen, S. R., Tajik, A. J., Gersh, B. J., Ackerman, M. J. Prevalence and spectrum of thin filament mutations in an outpatient referral population with hypertrophic cardiomyopathy. Circulation 108: 445-451, 2003. [PubMed: 12860912] [Full Text: https://doi.org/10.1161/01.CIR.0000080896.52003.DF]