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. 2003 Aug;40(8):560–567. doi: 10.1136/jmg.40.8.560

Expanding the phenotype of LMNA mutations in dilated cardiomyopathy and functional consequences of these mutations

P Sebillon 1, C Bouchier 1, L Bidot 1, G Bonne 1, K Ahamed 1, P Charron 1, V Drouin-Garraud 1, A Millaire 1, G Desrumeaux 1, A Benaiche 1, J Charniot 1, K Schwartz 1, E Villard 1, M Komajda 1
PMCID: PMC1735561  PMID: 12920062

Abstract

Aims: Mutations in the lamin A/C gene (LMNA) have been reported to be involved in dilated cardiomyopathy (DCM) associated with conduction system disease and/or skeletal myopathy. The aim of this study was to perform a mutational analysis of LMNA in a large white population of patients affected by dilated cardiomyopathy with or without associated symptoms.

Methods: We performed screening of the coding sequence of LMNA on DNA samples from 66 index cases, and carried out cell transfection experiments to examine the functional consequences of the mutations identified.

Results: A new missense (E161K) mutation was identified in a family with early atrial fibrillation and a previously described (R377H) mutation in another family with a quadriceps myopathy associated with DCM. A new mutation (28insA) leading to a premature stop codon was identified in a family affected by DCM with conduction defects. No mutation in LMNA was found in cases with isolated dilated cardiomyopathy. Functional analyses have identified potential physiopathological mechanisms involving identified mutations, such as haploinsufficiency (28insA) or intermediate filament disorganisation (E161K, R377H).

Conclusion: For the first time, a specific phenotype characterised by early atrial fibrillation is associated with LMNA mutation. Conversely, mutations in LMNA appear as a rare cause of isolated dilated cardiomyopathy. The variable phenotypes observed in LMNA-DCM might be explained by the variability of functional consequences of LMNA mutations.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Arbustini Eloisa, Pilotto Andrea, Repetto Alessandra, Grasso Maurizia, Negri Andrea, Diegoli Marta, Campana Carlo, Scelsi Laura, Baldini Elisa, Gavazzi Antonello. Autosomal dominant dilated cardiomyopathy with atrioventricular block: a lamin A/C defect-related disease. J Am Coll Cardiol. 2002 Mar 20;39(6):981–990. doi: 10.1016/s0735-1097(02)01724-2. [DOI] [PubMed] [Google Scholar]
  2. Bonne G., Di Barletta M. R., Varnous S., Bécane H. M., Hammouda E. H., Merlini L., Muntoni F., Greenberg C. R., Gary F., Urtizberea J. A. Mutations in the gene encoding lamin A/C cause autosomal dominant Emery-Dreifuss muscular dystrophy. Nat Genet. 1999 Mar;21(3):285–288. doi: 10.1038/6799. [DOI] [PubMed] [Google Scholar]
  3. Bonne G., Mercuri E., Muchir A., Urtizberea A., Bécane H. M., Recan D., Merlini L., Wehnert M., Boor R., Reuner U. Clinical and molecular genetic spectrum of autosomal dominant Emery-Dreifuss muscular dystrophy due to mutations of the lamin A/C gene. Ann Neurol. 2000 Aug;48(2):170–180. [PubMed] [Google Scholar]
  4. Brodsky G. L., Muntoni F., Miocic S., Sinagra G., Sewry C., Mestroni L. Lamin A/C gene mutation associated with dilated cardiomyopathy with variable skeletal muscle involvement. Circulation. 2000 Feb 8;101(5):473–476. doi: 10.1161/01.cir.101.5.473. [DOI] [PubMed] [Google Scholar]
  5. Bécane H. M., Bonne G., Varnous S., Muchir A., Ortega V., Hammouda E. H., Urtizberea J. A., Lavergne T., Fardeau M., Eymard B. High incidence of sudden death with conduction system and myocardial disease due to lamins A and C gene mutation. Pacing Clin Electrophysiol. 2000 Nov;23(11 Pt 1):1661–1666. doi: 10.1046/j.1460-9592.2000.01661.x. [DOI] [PubMed] [Google Scholar]
  6. Charniot Jean-Christophe, Pascal Cécile, Bouchier Christiane, Sébillon Pascale, Salama Jeffrey, Duboscq-Bidot Laëtitia, Peuchmaurd Mireille, Desnos Michel, Artigou Jean-Yves, Komajda Michel. Functional consequences of an LMNA mutation associated with a new cardiac and non-cardiac phenotype. Hum Mutat. 2003 May;21(5):473–481. doi: 10.1002/humu.10170. [DOI] [PubMed] [Google Scholar]
  7. Culbertson M. R. RNA surveillance. Unforeseen consequences for gene expression, inherited genetic disorders and cancer. Trends Genet. 1999 Feb;15(2):74–80. doi: 10.1016/s0168-9525(98)01658-8. [DOI] [PubMed] [Google Scholar]
  8. Daehmlow Steffen, Erdmann Jeanette, Knueppel Tanja, Gille Christoph, Froemmel Cornelius, Hummel Manfred, Hetzer Roland, Regitz-Zagrosek Vera. Novel mutations in sarcomeric protein genes in dilated cardiomyopathy. Biochem Biophys Res Commun. 2002 Oct 18;298(1):116–120. doi: 10.1016/s0006-291x(02)02374-4. [DOI] [PubMed] [Google Scholar]
  9. Dec G. W., Fuster V. Idiopathic dilated cardiomyopathy. N Engl J Med. 1994 Dec 8;331(23):1564–1575. doi: 10.1056/NEJM199412083312307. [DOI] [PubMed] [Google Scholar]
  10. Fatkin D., MacRae C., Sasaki T., Wolff M. R., Porcu M., Frenneaux M., Atherton J., Vidaillet H. J., Jr, Spudich S., De Girolami U. Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease. N Engl J Med. 1999 Dec 2;341(23):1715–1724. doi: 10.1056/NEJM199912023412302. [DOI] [PubMed] [Google Scholar]
  11. Favreau Catherine, Dubosclard Emmanuelle, Ostlund Cecilia, Vigouroux Corinne, Capeau Jacqueline, Wehnert Manfred, Higuet Dominique, Worman Howard J., Courvalin Jean-Claude, Buendia Brigitte. Expression of lamin A mutated in the carboxyl-terminal tail generates an aberrant nuclear phenotype similar to that observed in cells from patients with Dunnigan-type partial lipodystrophy and Emery-Dreifuss muscular dystrophy. Exp Cell Res. 2003 Jan 1;282(1):14–23. doi: 10.1006/excr.2002.5669. [DOI] [PubMed] [Google Scholar]
  12. Genschel J., Baier P., Kuepferling S., Proepsting M. J., Buettner C., Ewert R., Hetzer R., Lochs H., Schmidt H. H. A new frameshift mutation at codon 466 (1397delA) within the LMNA gene. Hum Mutat. 2000 Sep;16(3):278–278. [PubMed] [Google Scholar]
  13. Genschel J., Bochow B., Kuepferling S., Ewert R., Hetzer R., Lochs H., Schmidt H. A R644C mutation within lamin A extends the mutations causing dilated cardiomyopathy. Hum Mutat. 2001 Feb;17(2):154–154. doi: 10.1002/1098-1004(200102)17:2<154::AID-HUMU11>3.0.CO;2-R. [DOI] [PubMed] [Google Scholar]
  14. Gerull Brenda, Gramlich Michael, Atherton John, McNabb Mark, Trombitás Karoly, Sasse-Klaassen Sabine, Seidman J. G., Seidman Christine, Granzier Henk, Labeit Siegfried. Mutations of TTN, encoding the giant muscle filament titin, cause familial dilated cardiomyopathy. Nat Genet. 2002 Jan 14;30(2):201–204. doi: 10.1038/ng815. [DOI] [PubMed] [Google Scholar]
  15. Grünig E., Tasman J. A., Kücherer H., Franz W., Kübler W., Katus H. A. Frequency and phenotypes of familial dilated cardiomyopathy. J Am Coll Cardiol. 1998 Jan;31(1):186–194. doi: 10.1016/s0735-1097(97)00434-8. [DOI] [PubMed] [Google Scholar]
  16. Hershberger Ray E., Hanson Emily L., Jakobs Petra M., Keegan Hugh, Coates Kelly, Bousman Sylvia, Litt Michael. A novel lamin A/C mutation in a family with dilated cardiomyopathy, prominent conduction system disease, and need for permanent pacemaker implantation. Am Heart J. 2002 Dec;144(6):1081–1086. doi: 10.1067/mhj.2002.126737. [DOI] [PubMed] [Google Scholar]
  17. Jakobs P. M., Hanson E. L., Crispell K. A., Toy W., Keegan H., Schilling K., Icenogle T. B., Litt M., Hershberger R. E. Novel lamin A/C mutations in two families with dilated cardiomyopathy and conduction system disease. J Card Fail. 2001 Sep;7(3):249–256. doi: 10.1054/jcaf.2001.26339. [DOI] [PubMed] [Google Scholar]
  18. Kamisago M., Sharma S. D., DePalma S. R., Solomon S., Sharma P., McDonough B., Smoot L., Mullen M. P., Woolf P. K., Wigle E. D. Mutations in sarcomere protein genes as a cause of dilated cardiomyopathy. N Engl J Med. 2000 Dec 7;343(23):1688–1696. doi: 10.1056/NEJM200012073432304. [DOI] [PubMed] [Google Scholar]
  19. Keeling P. J., Gang Y., Smith G., Seo H., Bent S. E., Murday V., Caforio A. L., McKenna W. J. Familial dilated cardiomyopathy in the United Kingdom. Br Heart J. 1995 May;73(5):417–421. doi: 10.1136/hrt.73.5.417. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Knöll Ralph, Hoshijima Masahiko, Hoffman Hal M., Person Veronika, Lorenzen-Schmidt Ilka, Bang Marie-Louise, Hayashi Takeharu, Shiga Nobuyuki, Yasukawa Hideo, Schaper Wolfgang. The cardiac mechanical stretch sensor machinery involves a Z disc complex that is defective in a subset of human dilated cardiomyopathy. Cell. 2002 Dec 27;111(7):943–955. doi: 10.1016/s0092-8674(02)01226-6. [DOI] [PubMed] [Google Scholar]
  21. Li D., Czernuszewicz G. Z., Gonzalez O., Tapscott T., Karibe A., Durand J. B., Brugada R., Hill R., Gregoritch J. M., Anderson J. L. Novel cardiac troponin T mutation as a cause of familial dilated cardiomyopathy. Circulation. 2001 Oct 30;104(18):2188–2193. doi: 10.1161/hc4301.098285. [DOI] [PubMed] [Google Scholar]
  22. Li D., Tapscoft T., Gonzalez O., Burch P. E., Quiñones M. A., Zoghbi W. A., Hill R., Bachinski L. L., Mann D. L., Roberts R. Desmin mutation responsible for idiopathic dilated cardiomyopathy. Circulation. 1999 Aug 3;100(5):461–464. doi: 10.1161/01.cir.100.5.461. [DOI] [PubMed] [Google Scholar]
  23. Mangin L., Charron P., Tesson F., Mallet A., Dubourg O., Desnos M., Benaïsche A., Gayet C., Gibelin P., Davy J. M. Familial dilated cardiomyopathy: clinical features in French families. Eur J Heart Fail. 1999 Dec;1(4):353–361. doi: 10.1016/s1388-9842(99)00047-1. [DOI] [PubMed] [Google Scholar]
  24. Mestroni L., Maisch B., McKenna W. J., Schwartz K., Charron P., Rocco C., Tesson F., Richter A., Wilke A., Komajda M. Guidelines for the study of familial dilated cardiomyopathies. Collaborative Research Group of the European Human and Capital Mobility Project on Familial Dilated Cardiomyopathy. Eur Heart J. 1999 Jan;20(2):93–102. doi: 10.1053/euhj.1998.1145. [DOI] [PubMed] [Google Scholar]
  25. Mestroni L., Rocco C., Gregori D., Sinagra G., Di Lenarda A., Miocic S., Vatta M., Pinamonti B., Muntoni F., Caforio A. L. Familial dilated cardiomyopathy: evidence for genetic and phenotypic heterogeneity. Heart Muscle Disease Study Group. J Am Coll Cardiol. 1999 Jul;34(1):181–190. doi: 10.1016/s0735-1097(99)00172-2. [DOI] [PubMed] [Google Scholar]
  26. Michels V. V., Moll P. P., Miller F. A., Tajik A. J., Chu J. S., Driscoll D. J., Burnett J. C., Rodeheffer R. J., Chesebro J. H., Tazelaar H. D. The frequency of familial dilated cardiomyopathy in a series of patients with idiopathic dilated cardiomyopathy. N Engl J Med. 1992 Jan 9;326(2):77–82. doi: 10.1056/NEJM199201093260201. [DOI] [PubMed] [Google Scholar]
  27. 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 Apr;33(4):723–732. doi: 10.1006/jmcc.2000.1339. [DOI] [PubMed] [Google Scholar]
  28. 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 May 1;280(5364):750–752. doi: 10.1126/science.280.5364.750. [DOI] [PubMed] [Google Scholar]
  29. Olson Timothy M., Illenberger Susanne, Kishimoto Nina Y., Huttelmaier Stefan, Keating Mark T., Jockusch Brigitte M. Metavinculin mutations alter actin interaction in dilated cardiomyopathy. Circulation. 2002 Jan 29;105(4):431–437. doi: 10.1161/hc0402.102930. [DOI] [PubMed] [Google Scholar]
  30. Ostlund C., Bonne G., Schwartz K., Worman H. J. Properties of lamin A mutants found in Emery-Dreifuss muscular dystrophy, cardiomyopathy and Dunnigan-type partial lipodystrophy. J Cell Sci. 2001 Dec;114(Pt 24):4435–4445. doi: 10.1242/jcs.114.24.4435. [DOI] [PubMed] [Google Scholar]
  31. Raharjo W. H., Enarson P., Sullivan T., Stewart C. L., Burke B. Nuclear envelope defects associated with LMNA mutations cause dilated cardiomyopathy and Emery-Dreifuss muscular dystrophy. J Cell Sci. 2001 Dec;114(Pt 24):4447–4457. doi: 10.1242/jcs.114.24.4447. [DOI] [PubMed] [Google Scholar]
  32. Schmitt Joachim P., Kamisago Mitsuhiro, Asahi Michio, Li Guo Hua, Ahmad Ferhaan, Mende Ulrike, Kranias Evangelia G., MacLennan David H., Seidman J. G., Seidman Christine E. Dilated cardiomyopathy and heart failure caused by a mutation in phospholamban. Science. 2003 Feb 28;299(5611):1410–1413. doi: 10.1126/science.1081578. [DOI] [PubMed] [Google Scholar]
  33. Shinbane J. S., Wood M. A., Jensen D. N., Ellenbogen K. A., Fitzpatrick A. P., Scheinman M. M. Tachycardia-induced cardiomyopathy: a review of animal models and clinical studies. J Am Coll Cardiol. 1997 Mar 15;29(4):709–715. doi: 10.1016/s0735-1097(96)00592-x. [DOI] [PubMed] [Google Scholar]
  34. Speckman R. A., Garg A., Du F., Bennett L., Veile R., Arioglu E., Taylor S. I., Lovett M., Bowcock A. M. Mutational and haplotype analyses of families with familial partial lipodystrophy (Dunnigan variety) reveal recurrent missense mutations in the globular C-terminal domain of lamin A/C. Am J Hum Genet. 2000 Apr;66(4):1192–1198. doi: 10.1086/302836. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Tesson F., Sylvius N., Pilotto A., Dubosq-Bidot L., Peuchmaurd M., Bouchier C., Benaiche A., Mangin L., Charron P., Gavazzi A. Epidemiology of desmin and cardiac actin gene mutations in a european population of dilated cardiomyopathy. Eur Heart J. 2000 Nov;21(22):1872–1876. doi: 10.1053/euhj.2000.2245. [DOI] [PubMed] [Google Scholar]
  36. Tsubata S., Bowles K. R., Vatta M., Zintz C., Titus J., Muhonen L., Bowles N. E., Towbin J. A. Mutations in the human delta-sarcoglycan gene in familial and sporadic dilated cardiomyopathy. J Clin Invest. 2000 Sep;106(5):655–662. doi: 10.1172/JCI9224. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Vigouroux C., Auclair M., Dubosclard E., Pouchelet M., Capeau J., Courvalin J. C., Buendia B. Nuclear envelope disorganization in fibroblasts from lipodystrophic patients with heterozygous R482Q/W mutations in the lamin A/C gene. J Cell Sci. 2001 Dec;114(Pt 24):4459–4468. doi: 10.1242/jcs.114.24.4459. [DOI] [PubMed] [Google Scholar]

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