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Gene Review

Lmna  -  lamin A

Mus musculus

Synonyms: Dhe, Lmn1, Prelamin-A/C, lamin A/C
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Disease relevance of Lmna

  • Despite severe DCM, defects in nuclear function prevent Lmna(-/-) cardiomyocytes from developing compensatory hypertrophy and accelerate disease progression [1].
  • We further hypothesized that Zmpste24(-/-) mice with half-normal levels of prelamin A (Zmpste24(-/-) mice with one Lmna knockout allele) would be subjected to less toxicity and be protected from disease [2].
  • Lmna mutations have also recently been found in patients with atypical forms of progeria [3].
  • Lmna-/- mice, which die prematurely of muscular dystrophy, have little fat, but do not show the insulin resistance characteristic of FPLD [4].
  • In the mouse, a deficiency in both lamin A and lamin C leads to slow growth, muscle weakness, and death by 6 weeks of age [5].

High impact information on Lmna

  • This deficiency in prelamin A maturation leads to the generation of abnormalities in nuclear architecture that probably underlie the many phenotypes observed in both mice and humans with mutations in the lamin A gene [6].
  • Lamin A is a major component of the nuclear lamina and nuclear skeleton [7].
  • Truncation in lamin A causes Hutchinson-Gilford progerial syndrome (HGPS), a severe form of early-onset premature aging [7].
  • The Lmna mutation resulted in nuclear morphology defects and decreased lifespan of homozygous fibroblasts, suggesting premature cell death [8].
  • Here we describe the derivation of mice carrying an autosomal recessive mutation in the lamin A gene (Lmna) encoding A-type lamins, major components of the nuclear lamina [8].

Chemical compound and disease context of Lmna


Biological context of Lmna

  • To determine whether impaired myogenesis is linked to reduced MyoD or desmin levels, these proteins were individually expressed in Lmna(-/-) myoblasts that were then induced to undergo myogenesis [10].
  • Heterozygosity for Lmna deficiency eliminates the progeria-like phenotypes in Zmpste24-deficient mice [2].
  • Both pRB levels and localization are restored upon reintroduction of lamin A. Lmna(-/-) cells resemble Rb(-/-) cells, exhibiting altered cell-cycle properties and reduced capacity to undergo cell-cycle arrest in response to DNA damage [11].
  • An array of lamin A mutants, representing a variety of pathologies as well as lamin A processing mutants, was introduced into Lmna(-/-) cells [12].
  • In contrast, oogenesis remains largely unaffected in Lmna(-/-) mice [13].

Anatomical context of Lmna


Associations of Lmna with chemical compounds

  • Retinoic acid (RA)-induced differentiation of P19 embryonic carcinoma cells, in which A-type lamins are absent, increases the expression of lamin A/C [15].
  • CONCLUSIONS: We show in an adipose cell line that IDV and NFV induced alterations at the nuclear level by promoting defects in lamin A/C maturation, organization and stability [16].
  • NFV similarly altered lamin A/C maturation whereas APV was almost ineffective [16].
  • Ventricular myocytes isolated from Lmna(-/-) mice exhibited impaired contractile responses, particularly when superfused with the beta-adrenergic agonist, isoproterenol (1 microM) [17].
  • Here we analyze myoblast-to-myotube differentiation in C2C12 clones overexpressing lamin A mutated at arginine 453 (R453W), one of the most frequent mutations in EDMD [18].

Enzymatic interactions of Lmna

  • In our study, LLC-PK1 cells infected with CPV delta crmA, but not those infected with wt CPV, showed induction of poly(ADP-ribose) polymerase (PARP)- and lamin A-cleaving activities and processing of the CPP32 (caspase-3) precursor to a mature 18-kDa form [19].

Regulatory relationships of Lmna

  • NF-kappaB-regulated transcription in response to mechanical or cytokine stimulation was attenuated in Lmna-/- cells despite increased transcription factor binding [20].
  • The occurrence of nuclear abnormalities was reduced when lamin B1 was coexpressed with mutant lamin A, emphasizing the functional interaction of the two types of lamins [21].

Other interactions of Lmna

  • Mouse models, such as Lmna knockout, Zmpste24 knockout, and Lmna L530P knockin will help the study of progeria [3].
  • These findings suggest a model in which the primary pathophysiological mechanism in Lmna(-/-) mice is defective force transmission resulting from disruption of lamin interactions with the muscle-specific desmin network and loss of cytoskeletal tension [1].
  • Lmna(-/-) LV myocyte nuclei have marked alterations of shape and size with central displacement and fragmentation of heterochromatin; these changes are present but less severe in left atrial nuclei [1].
  • We expressed these proteins fused to green fluorescent protein in embryonic fibroblasts from wild-type mice and Lmna -/- mice, which lack A-type lamins [22].
  • Characterization of adiposity and metabolism in Lmna-deficient mice [4].

Analytical, diagnostic and therapeutic context of Lmna


  1. Defects in nuclear structure and function promote dilated cardiomyopathy in lamin A/C-deficient mice. Nikolova, V., Leimena, C., McMahon, A.C., Tan, J.C., Chandar, S., Jogia, D., Kesteven, S.H., Michalicek, J., Otway, R., Verheyen, F., Rainer, S., Stewart, C.L., Martin, D., Feneley, M.P., Fatkin, D. J. Clin. Invest. (2004) [Pubmed]
  2. Heterozygosity for Lmna deficiency eliminates the progeria-like phenotypes in Zmpste24-deficient mice. Fong, L.G., Ng, J.K., Meta, M., Coté, N., Yang, S.H., Stewart, C.L., Sullivan, T., Burghardt, A., Majumdar, S., Reue, K., Bergo, M.O., Young, S.G. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  3. Hutchinson-Gilford progeria syndrome. Pollex, R.L., Hegele, R.A. Clin. Genet. (2004) [Pubmed]
  4. Characterization of adiposity and metabolism in Lmna-deficient mice. Cutler, D.A., Sullivan, T., Marcus-Samuels, B., Stewart, C.L., Reitman, M.L. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  5. Prelamin A and lamin A appear to be dispensable in the nuclear lamina. Fong, L.G., Ng, J.K., Lammerding, J., Vickers, T.A., Meta, M., Coté, N., Gavino, B., Qiao, X., Chang, S.Y., Young, S.R., Yang, S.H., Stewart, C.L., Lee, R.T., Bennett, C.F., Bergo, M.O., Young, S.G. J. Clin. Invest. (2006) [Pubmed]
  6. Defective prelamin A processing and muscular and adipocyte alterations in Zmpste24 metalloproteinase-deficient mice. Pendás, A.M., Zhou, Z., Cadiñanos, J., Freije, J.M., Wang, J., Hultenby, K., Astudillo, A., Wernerson, A., Rodríguez, F., Tryggvason, K., López-Otín, C. Nat. Genet. (2002) [Pubmed]
  7. Genomic instability in laminopathy-based premature aging. Liu, B., Wang, J., Chan, K.M., Tjia, W.M., Deng, W., Guan, X., Huang, J.D., Li, K.M., Chau, P.Y., Chen, D.J., Pei, D., Pendas, A.M., Cadiñanos, J., López-Otín, C., Tse, H.F., Hutchison, C., Chen, J., Cao, Y., Cheah, K.S., Tryggvason, K., Zhou, Z. Nat. Med. (2005) [Pubmed]
  8. A progeroid syndrome in mice is caused by defects in A-type lamins. Mounkes, L.C., Kozlov, S., Hernandez, L., Sullivan, T., Stewart, C.L. Nature (2003) [Pubmed]
  9. Expression of prelamin A but not mature lamin A confers sensitivity of DNA biosynthesis to lovastatin on F9 teratocarcinoma cells. Sinensky, M., McLain, T., Fantle, K. J. Cell. Sci. (1994) [Pubmed]
  10. Lamin A/C and emerin are critical for skeletal muscle satellite cell differentiation. Frock, R.L., Kudlow, B.A., Evans, A.M., Jameson, S.A., Hauschka, S.D., Kennedy, B.K. Genes Dev. (2006) [Pubmed]
  11. A-type lamins regulate retinoblastoma protein function by promoting subnuclear localization and preventing proteasomal degradation. Johnson, B.R., Nitta, R.T., Frock, R.L., Mounkes, L., Barbie, D.A., Stewart, C.L., Harlow, E., Kennedy, B.K. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  12. Stabilization of the retinoblastoma protein by A-type nuclear lamins is required for INK4A-mediated cell cycle arrest. Nitta, R.T., Jameson, S.A., Kudlow, B.A., Conlan, L.A., Kennedy, B.K. Mol. Cell. Biol. (2006) [Pubmed]
  13. Disruption of spermatogenesis in mice lacking A-type lamins. Alsheimer, M., Liebe, B., Sewell, L., Stewart, C.L., Scherthan, H., Benavente, R. J. Cell. Sci. (2004) [Pubmed]
  14. Good news in the nuclear envelope: loss of lamin A might be a gain. Scaffidi, P., Misteli, T. J. Clin. Invest. (2006) [Pubmed]
  15. c-Jun and Sp1 family are critical for retinoic acid induction of the lamin A/C retinoic acid-responsive element. Okumura, K., Hosoe, Y., Nakajima, N. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  16. Some HIV protease inhibitors alter lamin A/C maturation and stability, SREBP-1 nuclear localization and adipocyte differentiation. Caron, M., Auclair, M., Sterlingot, H., Kornprobst, M., Capeau, J. AIDS (2003) [Pubmed]
  17. Skeletal and cardiac muscle defects in a murine model of Emery-Dreifuss muscular dystrophy. Grattan, M.J., Kondo, C., Thurston, J., Alakija, P., Burke, B.J., Stewart, C., Syme, D., Giles, W.R. Novartis Found. Symp. (2005) [Pubmed]
  18. Expression of a mutant lamin A that causes Emery-Dreifuss muscular dystrophy inhibits in vitro differentiation of C2C12 myoblasts. Favreau, C., Higuet, D., Courvalin, J.C., Buendia, B. Mol. Cell. Biol. (2004) [Pubmed]
  19. Activation of caspases in pig kidney cells infected with wild-type and CrmA/SPI-2 mutants of cowpox and rabbitpox viruses. Macen, J., Takahashi, A., Moon, K.B., Nathaniel, R., Turner, P.C., Moyer, R.W. J. Virol. (1998) [Pubmed]
  20. Lamin A/C deficiency causes defective nuclear mechanics and mechanotransduction. Lammerding, J., Schulze, P.C., Takahashi, T., Kozlov, S., Sullivan, T., Kamm, R.D., Stewart, C.L., Lee, R.T. J. Clin. Invest. (2004) [Pubmed]
  21. 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. Favreau, C., Dubosclard, E., Ostlund, C., Vigouroux, C., Capeau, J., Wehnert, M., Higuet, D., Worman, H.J., Courvalin, J.C., Buendia, B. Exp. Cell Res. (2003) [Pubmed]
  22. Dependence of diffusional mobility of integral inner nuclear membrane proteins on A-type lamins. Ostlund, C., Sullivan, T., Stewart, C.L., Worman, H.J. Biochemistry (2006) [Pubmed]
  23. A novel interaction between lamin A and SREBP1: implications for partial lipodystrophy and other laminopathies. Lloyd, D.J., Trembath, R.C., Shackleton, S. Hum. Mol. Genet. (2002) [Pubmed]
  24. Differential timing of nuclear lamin A/C expression in the various organs of the mouse embryo and the young animal: a developmental study. Röber, R.A., Weber, K., Osborn, M. Development (1989) [Pubmed]
  25. Properties of lamin A mutants found in Emery-Dreifuss muscular dystrophy, cardiomyopathy and Dunnigan-type partial lipodystrophy. Ostlund, C., Bonne, G., Schwartz, K., Worman, H.J. J. Cell. Sci. (2001) [Pubmed]
  26. Age-related changes in lamin A/C expression in the osteoarticular system: laminopathies as a potential new aging mechanism. Duque, G., Rivas, D. Mech. Ageing Dev. (2006) [Pubmed]
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