Abstract
Cardiomyopathy is caused by functional abnormalities of cardiac muscle, which include both extrinsic and intrinsic factors. The intrinsic factor involves mutations in genes playing roles in performance, regulation, or maintenance of cardiac function. Cardiomyopathy caused by the intrinsic factor is called idiopathic or primary cardiomyopathy, and there are several clinical types of primary cardiomyopathy including hypertrophic cardiomyopathy and dilated cardiomyopathy. Linkage studies and candidate gene approaches have deciphered the disease genes for hereditary primary cardiomyopathy: mutations in genes for components of sarcomere, sarcolemma, Z-disk, proteins of I band region, nuclear membrane, and transcriptional machinery. The most interesting findings are that mutations in different disease genes can be found in the same clinical types of cardiomyopathy and that mutations in the same disease gene can be found in different clinical types of cardiomyopathy. Functional analyses of disease-related mutations have revealed that characteristic functional alterations are associated with each clinical type of cardiomyopathy. In this review I focus on the cardiomyopathy-associated mutations found in genes for sarcomere and Z-disk elements and their functional relevance in the pathogenesis of primary cardiomyopathy.
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References
Maron BJ, Towbin JA, Thiene G, et al. Contemporary definitions and classification of the cardiomyopathies: an American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention. Circulation. 2006;113:1807–16.
Towbin JA, Bowles NE. The failing heart. Nature. 2002;415:227–33.
Ahmad F, Seidman JG, Seidman CE. The genetic basis for cardiac remodeling. Annu Rev Genomics Hum Genet. 2006;6:185–216.
Kimura A. Molecular basis of hereditary cardiomyopathy: abnormalities in calcium sensitivity, stretch response, stress response and beyond. J Hum Genet. 2010;55:81–90.
Geisterfer-Lowrance AAT, Kass S, Tanigawa G, et al. A molecular basis for familial hypertrophic cardiomyopathy: a beta cardiac myosin heavy chain gene missense mutation. Cell. 1990;62:999–1006.
Sweeney HL, Straceski AJ, Leinwand LA, et al. Heterologous expression of a cardiomyopathic myosin that is defective in its actin interaction. J Biol Chem. 1994;269:1603–5.
Thierfelder L, Watkins H, MacRae C, et al. Alpha-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere. Cell. 1994;77:701–12.
Kimura A, Harada H, Park JE, et al. Mutations in the cardiac troponin I gene associated with hypertrophic cardiomyopathy. Nat Genet. 1997;16:379–82.
Yanaga F, Morimoto S, Ohtsuki I. Ca2+ sensitization and potentiation of the maximum level of myofibrillar ATPase activity caused by mutations of troponin T found in familial hypertrophic cardiomyopathy. J Biol Chem. 1999;274:8806–12.
Bottinelli R, Coviello DA, Redwood CS, et al. A mutant tropomyosin that causes hypertrophic cardiomyopathy is expressed in vivo and associated with an increased calcium sensitivity. Circ Res. 1998;82:106–15.
Elliott K, Watkins H, Redwood CS. Altered regulatory properties of human cardiac troponin I mutants that cause hypertrophic cardiomyopathy. J Biol Chem. 2000;275:22069–74.
Witt CC, Gerull B, Davies MJ, et al. Hypercontractile properties of cardiac muscle fibers in a knock-in mouse model of cardiac myosin-binding protein-C. J Biol Chem. 2001;276:5353–9.
Roopnarine O. Mechanical defects of muscle fibers with myosin light chain mutants that cause cardiomyopathy. Biophys J. 2003;84:2440–9.
Pinto JR, Parvatiyar MS, Jones MA, et al. A functional and structural study of troponin C mutations related to hypertrophic cardiomyopathy. J Biol Chem. 2009;284:19090–100.
Tyska MJ, Hayes E, Giewat M, et al. Single-molecule mechanics of R403Q cardiac myosin isolated from the mouse model of familial hypertrophic cardiomyopathy. Circ Res. 2000;86:737–44.
Olson TM, Michels VV, Thibodeau SN, et al. Actin mutations in dilated cardiomyopathy, a heritable form of heart failure. Science. 1998;280:750–2.
Mogensen J, Klausen IC, Pedersen AK, et al. Alpha-cardiac actin is a novel disease gene in familial hypertrophic cardiomyopathy. J Clin Invest. 1999;103:R39–43.
Vang S, Corydon TJ, Børglum AD, et al. Actin mutations in hypertrophic and dilated cardiomyopathy cause inefficient protein folding and perturbed filament formation. FEBS J. 2005;272:2037–49.
Kamisago M, Sharma SD, DePalma SR, et al. Mutations in sarcomere protein genes as a cause of dilated cardiomyopathy. N Engl J Med. 2000;343:1688–96.
Morimoto S, Lu QW, Harada K, et al. Ca 2+-desensitizing effect of a deletion mutation Delta K210 in cardiac troponin T that causes familial dilated cardiomyopathy. Proc Natl Acad Sci USA. 2002;99:913–18.
Satoh M, Takahashi M, Sakamoto T, et al. Structural analysis of the titin gene in hypertrophic cardiomyopathy: identification of a novel disease gene. Biochem Biophys Res Commun. 1999;262:411–17.
Hayashi T, Arimura T, Itoh-Satoh M, et al. Tcap gene mutations in hypertrophic cardiomyopathy and dilated cardiomyopathy. J Am Coll Cardiol. 2004;44:2192–201.
Cazorla O, Wu Y, Irving TC, et al. Titin-based modulation of calcium sensitivity of active tension in mouse skinned cardiac myocytes. Circ Res. 2001;88:1028–35.
Fujita H, Labeit D, Gerull B, et al. Titin isoform-dependent effect of calcium on passive myocardial tension. Am J Physiol Heart Circ Physiol. 2004;287:H2528–34.
Fuchs F, Martyn DA. Length-dependent Ca 2+ activation in cardiac muscle: some remaining questions. J Muscle Res Cell Motil. 2005;26:199–212.
Itoh-Satoh M, Hayashi T, Nishi H, et al. Titin mutations as the molecular basis for dilated cardiomyopathy. Biochem Biophys Res Commun. 2002;291:385–93.
Knöll R, Hoshijima M, Hoffman HM, et al. The cardiac mechanical stretch sensor machinery involves a Z-disk complex that is defective in a subset of human dilated cardiomyopathy. Cell. 2002;111:943–55.
Geier C, Perrot A, Ozcelik C, et al. Mutations in the human muscle LIM protein gene in families with hypertrophic cardiomyopathy. Circulation. 2003;107:1390–5.
Gehmlich K, Geier C, Osterziel KJ, et al. Decreased interactions of mutant muscle LIM protein (MLP) with N-RAP and alpha-actinin and their implication for hypertrophic cardiomyopathy. Cell Tissue Res. 2004;317:129–36.
Mohapatra B, Jimenez S, Lin JH, et al. Mutations in the muscle LIM protein and alpha-actinin-2 genes in dilated cardiomyopathy and endocardial fibroelastosis. Mol Genet Metab. 2003;80:207–15.
Zhou Q, Ruiz-Lozano P, Martone ME, et al. Cypher, a striated muscle-restricted PDZ and LIM domain-containing protein, binds to alpha-actinin-2 and protein kinase C. J Biol Chem. 1999;274:19807–13.
Frey N, Richardson JA, Olson EN. Calsarcins, a novel family of sarcomeric calcineurin-binding proteins. Proc Natl Acad Sci USA. 2000;97:14632–7.
Wilkins BJ, Molkentin JD. Calcium-calcineurin signaling in the regulation of cardiac hypertrophy. Biochem Biophys Res Commun. 2004;322:1178–91.
Heineke J, Molkentin JD. Regulation of cardiac hypertrophy by intracellular signalling pathways. Nat Rev Mol Cell Biol. 2006;7:589–600.
Heineke J, Ruetten H, Willenbockel C, et al. Attenuation of cardiac remodeling after myocardial infarction by muscle LIM protein-calcineurin signaling at the sarcomeric Z-disk. Proc Natl Acad Sci U S A. 2005;102:1655–60.
Arimura T, Hayashi T, Terada H, et al. A Cypher/ZASP mutation associated with dilated cardiomyopathy alters the binding affinity to protein kinase C. J Biol Chem. 2004;279:6746–52.
Vatta M, Mohapatra B, Jimenez S, et al. Mutations in Cypher/ZASP in patients with dilated cardiomyopathy and left ventricular non-compaction. J Am Coll Cardiol. 2003;42:2014–27.
Arimura T, Inagaki N, Hayashi T, et al. Impaired binding of ZASP/Cypher with phosphoglucomutase 1 is associated with dilated cardiomyopathy. Cardiovasc Res. 2009;83:80–8.
Olson TM, Illenberger S, Kishimoto NY, et al. Metavinculin mutations alter actin interaction in dilated cardiomyopathy. Circulation. 2002;105:431–7.
Taylor MR, Slavov D, Ku L, et al. Prevalence of desmin mutations in dilated cardiomyopathy. Circulation. 2007;115:1244–51.
Duboscq-Bidot L, Xu P, Charron P, et al. Mutations in the Z-band protein myopalladin gene and idiopathic dilated cardiomyopathy. Cardiovasc Res. 2008;77:118–25.
Aihara Y, Kurabayashi M, Saito Y, et al. Cardiac ankyrin repeat protein is a novel marker of cardiac hypertrophy: role of M-CAT element within the promoter. Hypertension. 2000;36:48–53.
Witt SH, Labeit D, Granzier H, et al. Dimerization of the cardiac ankyrin protein CARP: implications for MARP titin-based signaling. J Muscle Res Cell Motil. 2006;262:1–8.
Arimura T, Bos MJ, Sato A, et al. Cardiac ankyrin repeat protein gene (ANKRD1) mutations in hypertrophic cardiomyopathy. J Am Coll Cardiol. 2009;54:334–42.
Neuhaus H, Rosen V, Thies R. Heart specific expression of mouse BMP-10 a novel member of the TGF-beta superfamily. Mech Dev. 1999;80:181–4.
Chen H, Shi S, Acosta L, et al. BMP10 is essential for maintaining cardiac growth during murine cardiogenesis. Development. 2004;131:2219–31.
Nakano N, Hori H, Abe M, et al. Interaction of BMP10 with Tcap may modulate the course of hypertensive cardiac hypertrophy. Am J Physiol Heart Card Physiol. 2007;293:H3396–403.
Nicholas G, Thomas M, Langley B, et al. Titin-cap associates with, and regulates secretion of, Myostatin. J Cell Physiol. 2002;193:120–31.
Acknowledgments
This work was supported in part by Grant-in-Aids for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan; research grant for Idiopathic Cardiomyopathy from the Ministry of Health, Labor and Welfare, Japan; grants for Basic Scientific Cooperation Program between Japan and Korea from the Japan Society for the Promotion of Science, the Korea Science and Engineering Foundation, and National Research Foundation of Korea; and research grants from the Institute of Life Science. This work was also supported by the follow-up grants provided from the Tokyo Medical and Dental University.
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Kimura, A. (2011). Cardiomyopathy, Sarcomeropathy, and Z-diskopathy. In: Ostadal, B., Nagano, M., Dhalla, N. (eds) Genes and Cardiovascular Function. Springer, Boston, MA. https://doi.org/10.1007/978-1-4419-7207-1_21
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DOI: https://doi.org/10.1007/978-1-4419-7207-1_21
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