Molecular Etiology of Idiopathic Cardiomyopathy

Identification of Novel Disease Genes in Hypertrophic Cardiomyopathy and Dilated Cardiomyopathy
  • Akinori Kimura
  • Takeharu Hayashil
  • Manatsu Itoh-Satohl
  • Takuro Arimura
  • Won-Ha Lee
  • Su Yeoun Lee
  • Jeong-Euy Park
Part of the Developments in Cardiovascular Medicine book series (DICM, volume 248)


Recent progress in molecular genetic research has revealed that mutations in components of sarcomere, affecting force generation or force transmission, cause hypertrophic cardiomyopathy (HCM) and/or dilated cardiomyopathy (DCM) at least in a certain percentage of familial cases. Our extensive analyses disease genes identified thus far among HCM and DCM patients have revealed a considerable number of mutations in Japanese and Korean populations. However, mutations have not been identified in many patients whose disease etiology is unknown, suggesting the presence of additional yet undiscovered diseased genes. In our search for mutations in several candidate genes in patient populations without mutations of known disease genes, we have identified several disease-related mutations in Z-disc components such as titin and telethonin in both HCM and DCM patients. Functional analyses of the titin and telethonin mutations have shown opposite functional changes between the HCM-related and DCM-related mutations. The HCM-related mutations increased the binding affinity of Z- disc components, while the OCM-related mutations decreased their affinity. These observations suggest that the titin and telethonin genes are new disease-genes implicated in both HCM and OCM, and that HCM is a disease of stiff sarcomere, whereas DCM may be a disease of loose sarcomere.


Dilate Cardiomyopathy Disease Gene Hypertrophic Cardiomyopathy Molecular Etiology Regulatory Light Chain Phosphorylation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Seidman JG, Seidman C. The Genetic Basis for Cardiomyopathy: From Mutation Identification to Mechanistic Paradigms. Cell 2001;104:557–567.PubMedCrossRefGoogle Scholar
  2. 2.
    Mestroni L, Rocco C, Gregori D, et al. Familial Dilated Cardiomyopathy: Evidence for Genetic and Phenotypic Heterogeneity. J Am Coll Cardiol 1999;34:181–190.PubMedCrossRefGoogle Scholar
  3. 3.
    Geisterfer-Lowrance AA, 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.PubMedCrossRefGoogle Scholar
  4. 4.
    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;77:701–712.PubMedCrossRefGoogle Scholar
  5. 5.
    Watkins H, Conner D, Thierfelder L, et al. Mutations in the Cardiac Myosin Binding Protein-C Gene on Chromosome 11 Cause Familial Hypertrophic Cardiomyopathy. Nature Genet 1995;11:434–437.PubMedCrossRefGoogle Scholar
  6. 6.
    Bonne G, Carrier L, Bercovici J, et al. Cardiac Myosin Binding Protein-C Gene Splice Acceptor Site Mutation is Associated with Hypertrophic Cardiomyopathy. Nature Genet 1995;11:438–440.PubMedCrossRefGoogle Scholar
  7. 7.
    Poetter K, Jiang H, Hassanzadeh S, et al. Mutations in Either the Essential or Regulatory Light Chain of Myosins are Associated with a Rare Myopathy in Human Heart and Skeletal Muscle. Nature Genet 1996;13:63–69.PubMedCrossRefGoogle Scholar
  8. 8.
    Kimura A, Harada H, Park JE, et al. Mutations in the Cardiac Troponin I Gene Associated with Hypertrophic Cardiomyopathy. Nature Genet 1997;16:379–382.PubMedCrossRefGoogle Scholar
  9. 9.
    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–R43.PubMedCrossRefGoogle Scholar
  10. 10.
    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;262:411–417.PubMedCrossRefGoogle Scholar
  11. 11.
    Blair E, Redwood C, Ashrafian H, et al. Mutations in the Gamma (2) Subunit of AMP-Activated Protein Kinase Cause Familial Hypertrophic Cardiomyopathy: Evidence for the Central Role of Energy Compromise in Disease Pathogenesis. Hum Mol Genet 2001;10:1215–1220.PubMedCrossRefGoogle Scholar
  12. 12.
    Davis JS, Hassanzadeh S, Winitsky S, et al. The Overall Pattern of Cardiac Contraction Depends on a Spatial Gradient of Myosin Regulatory Light Chain Phosphorylation. Cell 2001;107:631–641.PubMedCrossRefGoogle Scholar
  13. 13.
    Niimura H, Patton KK, McKenna WJ, et al. Sarcomere Protein Gene Mutations in Hypertrophic Cardiomyopathy of the Elderly. Circulation 2002;105:446–451.PubMedCrossRefGoogle Scholar
  14. 14.
    Fatkin D, et al. Missense Mutations in the Rod Domain of the Lamin A/C Gene as the Causes of Dilated Cardiomyopathy and Conduction-System Disease. N Engl J Med 1999;341:1715–1724.PubMedCrossRefGoogle Scholar
  15. 15.
    Li D, Tapscoft T, Gonzalez O, et al. Desmin Mutation Responsible for Idiopathic Dilated Cardiomyopathy. Circulation 1999;100:461–464.PubMedCrossRefGoogle Scholar
  16. 16.
    Tsubata S, et al. Mutations in the Human Delta-Sarcoglycan Gene in Familial and Sporadic Dilated Cardiomyopathy. J Clin Invest 2000;106:655–662.CrossRefGoogle Scholar
  17. 17.
    Olson TM, Illenberger S, Kishimoto NY, et al. Metavinculin Mutations Alter Actin Interaction in Dilated Cardiomyopathy. Circulation 2002;105:431–437.PubMedCrossRefGoogle Scholar
  18. 18.
    Olson TM, Michels VV, Thibodeau SN, et al. Actin Mutations in Dilated Cardiomyopathy, a Heritable Form of Heart Failure. Science 1998;280:750–752.PubMedCrossRefGoogle Scholar
  19. 19.
    Kamisago M, Sharma SD, DePalma SR, et al. Mutations in Sarcomere Protein Genes as a Cause of Dilated Cardiomyopathy. N Engl J Med 2000;343:1688–1696.PubMedCrossRefGoogle Scholar
  20. 20.
    Olson TM, Kishimoto NY, Whitby FG, et al. Mutations that Alter the Surface Charge of Alpha-Tropomyosin are Associated with Dilated Cardiomyopathy. J Mol Cell Cardiol 2001;33:723–732.PubMedCrossRefGoogle Scholar
  21. 21.
    Gerull B, Gramlich M, Atherton J, et al. Mutations of TTN, Encoding the Giant Muscle Filament Titin, Cause Familial Dilated Cardiomyopathy. Nature Genet 2002;30:201–204.PubMedCrossRefGoogle Scholar
  22. 22.
    Itoh-Satoh M, Hayashi T, Nishi H, et al. Titin Mutations as the Molecular Basis for Dilated Cardiomyopathy. Biochem Biophys Res Commun 2002;291:385–393.PubMedCrossRefGoogle Scholar
  23. 23.
    Taroni F, Verderio E, Fiorucci S, et al. Molecular Characterization of Inherited Carnitine Palmitoyltransferase II Deficiency. Proc Natl Acad Sci USA 1992;89:8429–8433.PubMedCrossRefGoogle Scholar
  24. 24.
    Norgett FE, Hatsell SJ, Carvajal-Huerta L, et al. Recessive Mutation in Desmoplakin Disrupts Desmoplakin-Intermediate Filament Interactions and Causes Dilated Cardiomyopathy, Woolly Hair and Keratoderma. Hum Mol Genet 2000;9:2761–2766.PubMedCrossRefGoogle Scholar
  25. 25.
    McKoy G, Protonotarios N, Crosby A, et al. Identification of a Deletion in Plakoglobin in Arrhythmogenic Right Ventricular Cardiomyopathy with Palmoplantar Keratoderma and Woolly Hair (Naxos disease). Lancet 2000;355:2119–2124.PubMedCrossRefGoogle Scholar
  26. 26.
    Towbin JA, Hejtmancik JF, Brink P, et al. X-linked Dilated Cardiomyopathy. Molecular Evidence of Linkage to the Duchenne Muscular Dystrophy (Dystrophin) Gene at the Xp21 Locus. Circulation 1993;87:1854–1865.PubMedCrossRefGoogle Scholar
  27. 27.
    Bione S, D’Adamo P, Maestrini E, et al. A Novel X-Linked Gene, G4.5, is Responsible for Barth Syndrome. Nature Genet 1996;12:385–389.PubMedCrossRefGoogle Scholar
  28. 28.
    Xu X, Meiler SE, Zhong TP, et al. Cardiomyopathy in Zebrafish Due to Mutation in Alternatively Spliced Exon of Titin. Nature Genet 2002;30:205–209.PubMedGoogle Scholar
  29. 29.
    Garvey SM, Rajan C, Lerner AP, et al. The Muscular Dystrophy with Myositis (mdm) Mouse Mutation Disrupts a Skeletal Muscle-Specific Domain of Titin. Genomics 2002;79:146–149.PubMedCrossRefGoogle Scholar
  30. 30.
    Gregorio CC, Trombitas K, Centner T, et al. The NH2 Terminus of Titin Spans the Z-Disc: Its Interaction with a Novel 19-kD Ligand (T-Cap) is Required for Sarcomere Integrity. J Cell Biol 1998;143:1013–1027.PubMedCrossRefGoogle Scholar
  31. 31.
    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;274:8806–8812.PubMedCrossRefGoogle Scholar
  32. 32.
    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;99:913–918.CrossRefGoogle Scholar
  33. 33.
    Mues A, van der Ven PF, Young P, et al. Two Immunoglobulin-Like Domains of the Z-Disc Portion of Titin Interact in a Conformation-Dependent Way with Titin. FEBS Lett 1998;428:111–114.PubMedCrossRefGoogle Scholar
  34. 34.
    Badorff C, Lee GH, Lamphear BJ, et al. Enteroviral Protease 2A Cleaves Dystrophin: Evidence of Cytoskeletal Disruption in an Acquired Cardiomyopathy. Nature Med 1999;5:320–326.PubMedCrossRefGoogle Scholar
  35. 35.
    Arber S, Hunter JJ, Ross J Jr, et al. MLP-Deficient Mice Exhibit a Disruption of Cardiac Cytoarchitectural Organization, Dilated Cardiomyopathy, and Heart Failure. Cell 1997;88:393–403.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2003

Authors and Affiliations

  • Akinori Kimura
    • 1
  • Takeharu Hayashil
    • 1
  • Manatsu Itoh-Satohl
    • 1
  • Takuro Arimura
    • 1
  • Won-Ha Lee
    • 2
  • Su Yeoun Lee
    • 2
  • Jeong-Euy Park
    • 2
  1. 1.Department of Molecular Pathogenesis, Medical Research InstituteTokyo Medical and Dental UniversityTokyoJapan
  2. 2.Department of Cardiovascular MedicineSamsung Medical Center, Sungkyunkwan University School of MedicineSeoulKorea

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