Logo of jmedgeneJournal of Medical GeneticsVisit this articleSubmit a manuscriptReceive email alertsContact usBMJ
J Med Genet. 2003 Aug; 40(8): 560–567.
PMCID: PMC1735561

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


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.

Full Text

The Full Text of this article is available as a PDF (266K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Dec GW, Fuster V. Idiopathic dilated cardiomyopathy. N Engl J Med. 1994 Dec 8;331(23):1564–1575. [PubMed]
  • Michels VV, Moll PP, Miller FA, Tajik AJ, Chu JS, Driscoll DJ, Burnett JC, Rodeheffer RJ, Chesebro JH, Tazelaar HD. 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. [PubMed]
  • Keeling PJ, Gang Y, Smith G, Seo H, Bent SE, Murday V, Caforio AL, McKenna WJ. Familial dilated cardiomyopathy in the United Kingdom. Br Heart J. 1995 May;73(5):417–421. [PMC free article] [PubMed]
  • Grünig E, Tasman JA, Kücherer H, Franz W, Kübler W, Katus HA. Frequency and phenotypes of familial dilated cardiomyopathy. J Am Coll Cardiol. 1998 Jan;31(1):186–194. [PubMed]
  • Olson TM, Michels VV, Thibodeau SN, Tai YS, Keating MT. Actin mutations in dilated cardiomyopathy, a heritable form of heart failure. Science. 1998 May 1;280(5364):750–752. [PubMed]
  • Li D, Tapscoft T, Gonzalez O, Burch PE, Quiñones MA, Zoghbi WA, Hill R, Bachinski LL, Mann DL, Roberts R. Desmin mutation responsible for idiopathic dilated cardiomyopathy. Circulation. 1999 Aug 3;100(5):461–464. [PubMed]
  • Tsubata S, Bowles KR, Vatta M, Zintz C, Titus J, Muhonen L, Bowles NE, Towbin JA. Mutations in the human delta-sarcoglycan gene in familial and sporadic dilated cardiomyopathy. J Clin Invest. 2000 Sep;106(5):655–662. [PMC free article] [PubMed]
  • Kamisago M, Sharma SD, DePalma SR, Solomon S, Sharma P, McDonough B, Smoot L, Mullen MP, Woolf PK, Wigle ED, et al. Mutations in sarcomere protein genes as a cause of dilated cardiomyopathy. N Engl J Med. 2000 Dec 7;343(23):1688–1696. [PubMed]
  • Li D, Czernuszewicz GZ, Gonzalez O, Tapscott T, Karibe A, Durand JB, Brugada R, Hill R, Gregoritch JM, Anderson JL, et al. Novel cardiac troponin T mutation as a cause of familial dilated cardiomyopathy. Circulation. 2001 Oct 30;104(18):2188–2193. [PubMed]
  • 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. [PubMed]
  • Olson TM, Kishimoto NY, Whitby FG, Michels VV. Mutations that alter the surface charge of alpha-tropomyosin are associated with dilated cardiomyopathy. J Mol Cell Cardiol. 2001 Apr;33(4):723–732. [PubMed]
  • Gerull Brenda, Gramlich Michael, Atherton John, McNabb Mark, Trombitás Karoly, Sasse-Klaassen Sabine, Seidman JG, Seidman Christine, Granzier Henk, Labeit Siegfried, et al. Mutations of TTN, encoding the giant muscle filament titin, cause familial dilated cardiomyopathy. Nat Genet. 2002 Feb;30(2):201–204. [PubMed]
  • 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. [PubMed]
  • Knöll Ralph, Hoshijima Masahiko, Hoffman Hal M, Person Veronika, Lorenzen-Schmidt Ilka, Bang Marie-Louise, Hayashi Takeharu, Shiga Nobuyuki, Yasukawa Hideo, Schaper Wolfgang, et al. 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. [PubMed]
  • Schmitt Joachim P, Kamisago Mitsuhiro, Asahi Michio, Li Guo Hua, Ahmad Ferhaan, Mende Ulrike, Kranias Evangelia G, MacLennan David H, Seidman JG, Seidman Christine E. Dilated cardiomyopathy and heart failure caused by a mutation in phospholamban. Science. 2003 Feb 28;299(5611):1410–1413. [PubMed]
  • Bonne G, Di Barletta MR, Varnous S, Bécane HM, Hammouda EH, Merlini L, Muntoni F, Greenberg CR, Gary F, Urtizberea JA, et al. Mutations in the gene encoding lamin A/C cause autosomal dominant Emery-Dreifuss muscular dystrophy. Nat Genet. 1999 Mar;21(3):285–288. [PubMed]
  • Bécane HM, Bonne G, Varnous S, Muchir A, Ortega V, Hammouda EH, Urtizberea JA, Lavergne T, Fardeau M, Eymard B, et al. 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. [PubMed]
  • Fatkin D, MacRae C, Sasaki T, Wolff MR, Porcu M, Frenneaux M, Atherton J, Vidaillet HJ, Jr, Spudich S, De Girolami U, et al. 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. [PubMed]
  • Arbustini Eloisa, Pilotto Andrea, Repetto Alessandra, Grasso Maurizia, Negri Andrea, Diegoli Marta, Campana Carlo, Scelsi Laura, Baldini Elisa, Gavazzi Antonello, et al. 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. [PubMed]
  • 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. [PubMed]
  • Jakobs PM, Hanson EL, Crispell KA, Toy W, Keegan H, Schilling K, Icenogle TB, Litt M, Hershberger RE. Novel lamin A/C mutations in two families with dilated cardiomyopathy and conduction system disease. J Card Fail. 2001 Sep;7(3):249–256. [PubMed]
  • 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. [PubMed]
  • Genschel J, Baier P, Kuepferling S, Proepsting MJ, Buettner C, Ewert R, Hetzer R, Lochs H, Schmidt HH. A new frameshift mutation at codon 466 (1397delA) within the LMNA gene. Hum Mutat. 2000 Sep;16(3):278–278. [PubMed]
  • 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. [PubMed]
  • Raharjo WH, Enarson P, Sullivan T, Stewart CL, 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. [PubMed]
  • Ostlund C, Bonne G, Schwartz K, Worman HJ. 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. [PubMed]
  • Vigouroux C, Auclair M, Dubosclard E, Pouchelet M, Capeau J, Courvalin JC, 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. [PubMed]
  • 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. [PubMed]
  • Mangin L, Charron P, Tesson F, Mallet A, Dubourg O, Desnos M, Benaïsche A, Gayet C, Gibelin P, Davy JM, et al. Familial dilated cardiomyopathy: clinical features in French families. Eur J Heart Fail. 1999 Dec;1(4):353–361. [PubMed]
  • Mestroni L, Rocco C, Gregori D, Sinagra G, Di Lenarda A, Miocic S, Vatta M, Pinamonti B, Muntoni F, Caforio AL, et al. Familial dilated cardiomyopathy: evidence for genetic and phenotypic heterogeneity. Heart Muscle Disease Study Group. J Am Coll Cardiol. 1999 Jul;34(1):181–190. [PubMed]
  • Mestroni L, Maisch B, McKenna WJ, 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. [PubMed]
  • Bonne G, Mercuri E, Muchir A, Urtizberea A, Bécane HM, Recan D, Merlini L, Wehnert M, Boor R, Reuner U, et al. 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]
  • Tesson F, Sylvius N, Pilotto A, Dubosq-Bidot L, Peuchmaurd M, Bouchier C, Benaiche A, Mangin L, Charron P, Gavazzi A, et al. Epidemiology of desmin and cardiac actin gene mutations in a european population of dilated cardiomyopathy. Eur Heart J. 2000 Nov;21(22):1872–1876. [PubMed]
  • Brodsky GL, 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. [PubMed]
  • Shinbane JS, Wood MA, Jensen DN, Ellenbogen KA, Fitzpatrick AP, Scheinman MM. Tachycardia-induced cardiomyopathy: a review of animal models and clinical studies. J Am Coll Cardiol. 1997 Mar 15;29(4):709–715. [PubMed]
  • Speckman RA, Garg A, Du F, Bennett L, Veile R, Arioglu E, Taylor SI, Lovett M, Bowcock AM. 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. [PMC free article] [PubMed]
  • Culbertson MR. RNA surveillance. Unforeseen consequences for gene expression, inherited genetic disorders and cancer. Trends Genet. 1999 Feb;15(2):74–80. [PubMed]

Articles from Journal of Medical Genetics are provided here courtesy of BMJ Group


Save items

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • Cited in Books
    Cited in Books
    NCBI Bookshelf books that cite the current articles.
  • ClinVar
    Clinical variations associated with publication
  • Gene
    Gene records that cite the current articles. Citations in Gene are added manually by NCBI or imported from outside public resources.
  • GEO Profiles
    GEO Profiles
    Gene Expression Omnibus (GEO) Profiles of molecular abundance data. The current articles are references on the Gene record associated with the GEO profile.
  • HomoloGene
    HomoloGene clusters of homologous genes and sequences that cite the current articles. These are references on the Gene and sequence records in the HomoloGene entry.
  • MedGen
    Related information in MedGen
  • OMIM
    Genome Survey Sequence (GSS) nucleotide records reported in the current articles.
  • Protein
    Protein translation features of primary database (GenBank) nucleotide records reported in the current articles as well as Reference Sequences (RefSeqs) that include the articles as references.
  • PubMed
    PubMed citations for these articles

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...