Genetics of dilated cardiomyopathy

Figures & data

Figure 1. A schematic structure of the myocyte. Dilated cardiomyopathy(DCM)‐associated proteins are marked by italic font.

Table I. Chromosomal loci, clinical characteristics and suggested disease‐causing mechanisms associated with DCM.

Locus	Gene	Clinical characteristics	Disease‐causing mechanism	Reference
1p1‐q21	Lamin A/C	CSD, SCD, LBBB, SVT, SMD, AF, PM, HT, SCD	Nuclear membrane damage leads to disruption of the cell causing myocyte death and tissue damage, loss of protein expression, altered localization of protein at the inner nuclear membrane, dysregulation of cellular functions	(20,25,26,29,32,43,50–52,54,116,154)
1q32	Troponin T	DCM, CSD, AF, SCD	Affects troponin C binding and diminished activation of calcium‐stimulated actomyosin ATPase	(28,30,35,65,155)
1q42‐q43	α‐Actinin	DCM, early onset	Disrupts the interaction with CLP and inhibits α‐actinin function	(41)
2q14‐q22	?	CSD		(156)
2q31	Titin	DCM, ICD, CSD, arrhythmias	Disrupts core sequence of immunoglobulin fold near Z‐disc–I‐band transition zone, decreases the binding affinity of titin to telethonin and α‐actinin, mutations in the cardiac‐specific region of titin cause truncated nonfunctional molecule	(27,68,71,157)
2q35	Desmin	DCM, muscular dystrophy, early onset		(34,75)
3p21	Troponin C	DCM, severe disease	Impairs troponin interaction leading to altered contractility	(46)
3p22‐p25	SCN5A	CSD, DCM		(45,158)
5q33	δ‐Sarcoglycan	DCM, SCD, early onset, mild disease	Alters the secondary structure of the protein	(56)
6q12‐q16	?			(159)
6q22.1	Phospholamban	DCM		(40)
6q23	?	Sensorineural hearing loss, skeletal myopathy, CSD		(160)
9q13‐q22	?	DCM		(161)
10q21‐23	?	Mitral valve prolapse		(162)
10q22‐q23	Metavinculin	DCM, HT	Disrupts force transmission at the thin filament‐intercalated disc interface	(38)
10q22.2‐23.3	Cypher/ZASP	DCM, LVH, CSD	Disarray of actin cytoskeleton	(48,103)
11p11	Myosin‐binding protein‐C	DCM, variable phenotype, SCD	Affects tropomyosin‐binding domain, truncates A band	(23)
11p15	Cardiac muscle LIM protein	DCM, early onset	Defect in the CLP/telethonin interaction → interferes stretch sensor machinery; abolishes interaction between MLP and α‐actinin, changes localization of MLP	(33,41)
12p12	Regulatory SUR2A subunit of cardiac KATP channel	DCM, VT	Disrupts catalysis‐dependent gating and impairs metabolic decoding, establishing a therefore unrecognized mechanism of channel malfunction	(49)
12q22	Thymopoietin	DCM, severe disease	Affects LAP2α and A‐type lamin binding	(47)
14q12	β‐Myosin heavy chain	DCM, HT, SCD, early onset HCM/DCM	Disrupts interactions between actin and myosin; alters the magnitude or polarity of transmitted movement → efficiency of contraction ↓; affects the ATP‐binding site	(23,30,62,63
15q14	Cardiac actin	DCM	Defect in force transmission	(36)
15q22	α‐Tropomyosin	DCM, variable phenotype, early onset, HT, SCD	Alters the interaction between actin and tropomyosin or compromised structural integrity	(37)
17q12	Telethonin	DCM, SCD, early onset	Loss of interaction between cardiac muscle LIM protein and telethonin	(33)
19q13	Troponin I	Recessive DCM, severe disease	Impairs interaction between troponin I and troponin T→contraction ↓	(42)
Xp21	Dystrophin	Skeletal muscle disease or isolated DCM, HT, SCD, early‐onset DCM	Affects the structural and functional integrity of myocyte sarcolemma; changes polarity (alters the secondary and tertiary structure of dystrophin), affects dystrophin expression in the heart	(18,19)
Xq28	Tafazzin	Endocardial fibroelastosis, Barth syndrome, left ventricular noncompaction		(21,24)

AF = atrial fibrillation; CSD = conduction system disease; DCM = dilated cardiomyopathy; HCM = hypertrophic cardiomyopathy; HT = heart transplantation; ICD = implantable cardioverter‐defibrillator; LBBB = left bundle branch block; LVH = left ventricular hypertrophy; PM = pacemaker; SCD = sudden cardiac death; SMD = skeletal muscle disease; SVT = supraventricular tachycardia; VT = ventricular tachycardia.

Figure 2. A schematic figure of the Dilated cardiomyopathy(DCM)‐causing mechanisms.

Arbustini E., Pilotto A., Repetto A., Grasso M., Negri A., Diegoli M., et al. Autosomal dominant dilated cardiomyopathy with atrioventricular block: a lamin A/C defect‐related disease. J Am Coll Cardiol 2002; 39: 981–90

 PubMed Web of Science ®Google Scholar

Jakobs P. M., Hanson E. L., Crispell K. A., Toy W., Keegan H., Schilling K., et al. Novel lamin A/C mutations in two families with dilated cardiomyopathy and conduction system disease. J Card Fail 2001; 7: 249–56

 Web of Science ®Google Scholar

Kärkkäinen S., Heliö T., Miettinen R., Tuomainen P., Peltola P., Rummukainen J., et al. A novel mutation, Ser143Pro, in the lamin A/C gene is common in finnish patients with familial dilated cardiomyopathy. Eur Heart J 2004; 25: 885–93

 Google Scholar

Michels V. V., Moll P. P., Miller F. A., Tajik A. J., Chu J. S., Driscoll D. J., et al. The frequency of familial dilated cardiomyopathy in a series of patients with idiopathic dilated cardiomyopathy. N Engl J Med 1992; 326: 77–82

 PubMed Web of Science ®Google Scholar

Karkkainen S., Reissell E., Helio T., Kaartinen M., Tuomainen P., Toivonen L., et al. Novel mutations in the lamin A/C gene in heart transplant recipients with end stage dilated cardiomyopathy. Heart 2006; 92: 524–526

 PubMed Web of Science ®Google Scholar

van Berlo J. H., deVoogt W. G., van der Kooi A. J., van Tintelen J. P., Bonne G., Yaou R. B., et al. Meta‐analysis of clinical characteristics of 299 carriers of LMNA gene mutations: do lamin A/C mutations portend a high risk of sudden death?. J Mol Med 2005; 83: 79–83

 PubMed Web of Science ®Google Scholar

Sebillon P., Bouchier C., Bidot L., Bonne G., Ahamed K., Charron P. Expanding the phenotype of LMNA mutations in dilated cardiomyopathy and functional consequences of these mutations. J Med Genet 2003; 40: 560–7

 PubMed Web of Science ®Google Scholar

Hanson E. L., Jakobs P. M., Keegan H., Coates K., Bousman S., Dienel N. H., et al. Cardiac troponin T lysine 210 deletion in a family with dilated cardiomyopathy. J Card Fail 2002; 8: 28–32

 Google Scholar

Kamisago M., Sharma S. D., DePalma S. R., Solomon S., Sharma P., McDonough B., et al. Mutations in Sarcomere Protein Genes as a Cause of Dilated Cardiomyopathy. N Engl J Med 2000; 343: 1688–96

 PubMed Web of Science ®Google Scholar

Li D., Czernuszewicz G. Z., Gonzalez O., Tapscott T., Karibe A., Durand J. B., et al. Novel cardiac troponin T mutation as a cause of familial dilated cardiomyopathy. Circulation 2001; 104: 2188–93

 PubMed Web of Science ®Google Scholar

Stefanelli C., Rosenthal A., Borisov A., Ensing G., Russell M. Novel troponin T mutation in familial dilated cardiomyopathy with gender‐dependant severity. Mol Genet Metab 2004; 83: 188–96

 PubMed Web of Science ®Google Scholar

Durand J. B., Bachinski L. L., Bieling L. C., Czernuszewicz G. Z., Abchee A. B., Yu Q. T., et al. Localization of a gene responsible for familial dilated cardiomyopathy to chromosome 1q32. Circulation 1995; 92: 3387–9

 PubMedGoogle Scholar

Mohapatra B., Jimenez S., Lin J. H., Bowles K. R., Coveler K. J., Marx J. G., 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

 PubMed Web of Science ®Google Scholar

Jung M., Poepping I., Perrot A., Ellmer A. E., Wienker T. F., Dietz R., et al. Investigation of a Family with Autosomal Dominant Dilated Cardiomyopathy Defines a Novel Locus on Chromosome 2q14–q22. Am J Hum Genet 1999; 65: 1068–77

 Google Scholar

Gerull B., Gramlich M., Atherton J., McNabb M., Trombitas K., Sasse‐Klaassen S., et al. Mutations of TTN, encoding the giant muscle filament titin, cause familial dilated cardiomyopathy. Nat Genet 2002; 14: 14

 Google Scholar

Itoh‐Satoh M., Hayashi T., Nishi H., Koga Y., Arimura T., Koyanagi T., et al. Titin mutations as the molecular basis for dilated cardiomyopathy. Biochem Biophys Res Commun 2002; 291: 385–93

 PubMed Web of Science ®Google Scholar

Gerull B., Atherton J., Geupel A., Sasse‐Klaassen S., Heuser A., Frenneaux M., et al. Identification of a novel frameshift mutation in the giant muscle filament titin in a large Australian family with dilated cardiomyopathy. J Mol Med 2006; 84: 478–83

 Google Scholar

Siu B. L., Niimura H., Osborne J. A., Fatkin D., MacRae C., Solomon S., et al. Familial dilated cardiomyopathy locus maps to chromosome 2q31. Circulation 1999; 99: 1022–6

 PubMed Web of Science ®Google Scholar

Li D., Tapscoft T., Gonzalez O., Burch P. E., Quinones M. A., Zoghbi W. A., et al. Desmin mutation responsible for idiopathic dilated cardiomyopathy. Circulation 1999; 100: 461–4

 PubMed Web of Science ®Google Scholar

Miyamoto Y., Akita H., Shiga N., Takai E., Iwai C., Mizutani K., et al. Frequency and clinical characteristics of dilated cardiomyopathy caused by desmin gene mutation in a Japanese population. Eur Heart J 2001; 22: 2284–9

 Google Scholar

Mogensen J., Murphy R., Shaw T., Bahl A., Redwood C., Watkins H., et al. Severe disease expressing of cardiac troponin C and T mutations in patients with idiopathic dilated cardiomyopathy. J Am Coll Cardiol 2004; 44: 2033–40

 PubMed Web of Science ®Google Scholar

McNair W., Ku T., Taylor M., Fain P., Dao D., Wolfel E., et al. SCN5A mutation associated with dilated cardiomyopathy, conduction disorder, and arrhythmia. Circulation 2004; 110: 2163–7

 PubMed Web of Science ®Google Scholar

Olson T. M., Keating M. T. Mapping a cardiomyopathy locus to chromosome 3p22-p25. J Clin Invest 1996; 97: 528–32

 Google Scholar

Tsubata S., Bowles K. R., Vatta M., Zintz C., Titus J., Muhonen L., et al. Mutations in the human delta‐sarcoglycan gene in familial and sporadic dilated cardiomyopathy. J Clin Invest 2000; 106: 655–62

 PubMed Web of Science ®Google Scholar

Sylvius N., Tesson F., Gayet C., Charron P., Benaiche A., Peuchmaurd M., et al. A New Locus for Autosomal Dominant Dilated Cardiomyopathy Identified on Chromosome 6q12–q16. Am J Hum Genet 2001; 68: 241–6

 Google Scholar

Schmitt J. P., Kamisago M., Asahi M., Li G. H., Ahmad F., Mende U., et al. Dilated cardiomyopathy and heart failure caused by a mutation in phospholamban. Science 2003; 299: 1410–3

 PubMed Web of Science ®Google Scholar

Messina D. N., Speer M. C., Pericak‐Vance M. A., McNally E. M. Linkage of familial dilated cardiomyopathy with conduction defect and muscular dystrophy to chromosome 6q23. Am J Hum Genet 1997; 61: 909–17

 Google Scholar

Krajinovic M., Pinamonti B., Sinagra G., Vatta M., Severini G. M., Milasin J., et al. Linkage of familial dilated cardiomyopathy to chromosome 9. Heart Muscle Disease Study Group. Am J Hum Genet 1995; 57: 846–52

 Google Scholar

Bowles K. R., Gajarski R., Porter P., Goytia V., Bachinski L., Roberts R., et al. Gene mapping of familial autosomal dominant dilated cardiomyopathy to chromosome 10q21–23. J Clin Invest 1996; 98: 1355–60

 PubMedGoogle Scholar

Olson T. M., Illenberger S., Kishimoto N. Y., Huttelmaier S., Keating M. T., Jockusch B. M. Metavinculin mutations alter actin interaction in dilated cardiomyopathy. Circulation 2002; 105: 431–7

 PubMed Web of Science ®Google Scholar

Vatta M., Mohapatra B., Jimenez S., Sanchez X., Faulkner G., Perles Z., et al. Mutations in Cypher/ZASP in patients with dilated cardiomyopathy and left ventricular non‐compaction. J Am Coll Cardiol 2003; 42: 2014–17

 PubMed Web of Science ®Google Scholar

Arimura T., Hayashi T., Terada H., Lee S‐Y., Zhou Q., Takahashi M., et al. A Cypher/ZASP mutation associated with dilated cardiomyopathy alters the binding affinity to protein kinase. J Biol Chem 2004; 279: 6746–52

 Google Scholar

Daehmlow S., Erdmann J., Knueppel T., Gille C., Froemmel C., Hummel M., et al. Novel mutations in sarcomeric protein genes in dilated cardiomyopathy. Biochem Biophys Res Commun 2002; 298: 116

 PubMed Web of Science ®Google Scholar

Knöll R., Hoshijima M., Hoffman H., Person V., Lorenzen‐Schmidt I., Bang M. The cardiac mechanical stretch sensor machinery involves a z disc complex that is defective in a subset of human dilated cardiomyopathy. Cell 2002; 111: 943–55

 PubMed Web of Science ®Google Scholar

Bienengraeber M., Olson T. M., Selivanov V. A., Kathmann E. C., O'Cochlain F., Gao F., et al. ABCC9 mutations identified in human dilated cardiomyopathy disrupt catalytic K(ATP) channel gating. Nat Genet 2004; 36: 382–7

 PubMed Web of Science ®Google Scholar

Taylor M., Slavov D., Gajewski A., Vlcek S., Ku L., Fain P., et al. Thymopoietin (lamina‐associated polypeptide 2) gene mutation associated with dilated cardiomyopathy. Hum Mutat 2005; 26: 566–74

 PubMed Web of Science ®Google Scholar

Olson T. M., Michels V. V., Thibodeau S. N., Tai Y. S., Keating M. T. Actin mutations in dilated cardiomyopathy, a heritable form of heart failure. Science 1998; 280: 750–2

 PubMed Web of Science ®Google Scholar

Olson T. M., Kishimoto N. Y., Whitby F. G., Michels V. V. Mutations that Alter the Surface Charge of Alpha‐tropomyosin are Associated with Dilated Cardiomyopathy. J Mol Cell Cardiol 2001; 33: 723–32

 PubMed Web of Science ®Google Scholar

Murphy R. T., Mogensen J., Shaw A., Kubo T., Hughes S., McKenna W. J. Novel mutation in cardiac troponin I in recessive idiopathic dilated cardiomyopathy. Lancet 2004; 363: 371–2

 PubMed Web of Science ®Google Scholar

Bione S., D'Adamo P., Maestrini E., Gedeon A. K., Bolhuis P. A., Toniolo D. A novel X‐linked gene, G4.5. is responsible for Barth syndrome. Nat Genet 1996; 12: 385–9

 PubMed Web of Science ®Google Scholar

D'Adamo P., Fassone L., Gedeon A., Janssen E. A., Bione S., Bolhuis P. A., et al. The X‐linked gene G4.5 is responsible for different infantile dilated cardiomyopathies. Am J Hum Genet 1997; 61: 862–7

 PubMed Web of Science ®Google Scholar