From Wikipedia, the free encyclopedia
Jump to: navigation, search
Lamin A/C
Protein LMNA PDB 1ifr.png
PDB rendering based on 1ifr.
Available structures
PDB Ortholog search: PDBe, RCSB
External IDs OMIM150330 MGI96794 HomoloGene41321 ChEMBL: 1293235 GeneCards: LMNA Gene
RNA expression pattern
PBB GE LMNA 203411 s at tn.png
PBB GE LMNA 212086 x at tn.png
PBB GE LMNA 214213 x at tn.png
More reference expression data
Species Human Mouse
Entrez 4000 16905
Ensembl ENSG00000160789 ENSMUSG00000028063
UniProt P02545 P48678
RefSeq (mRNA) NM_001257374 NM_001002011
RefSeq (protein) NP_001244303 NP_001002011
Location (UCSC) Chr 1:
156.05 – 156.11 Mb
Chr 3:
88.48 – 88.51 Mb
PubMed search [1] [2]

Lamin A/C also known as LMNA is a protein that in humans is encoded by the LMNA gene.[1][2] Lamin A/C belongs to the lamin family of proteins.


Biogenesis of lamin A in normal cells and the failure to generate mature lamin A in Hutchinson-Gilford progeria syndrome. In the setting of ZMPSTE24 deficiency, the final step of lamin processing does not occur, resulting in an accumulation of farnesyl-prelamin A. In Hutchinson-Gilford progeria syndrome, a 50-amino acid deletion in prelamin A (amino acids 607–656) removes the site for the second endoproteolytic cleavage. Consequently, no mature lamin A is formed, and a farnesylated mutant prelamin A (progerin) accumulates in cells.[3]

The nuclear lamina consist of a two-dimensional matrix of proteins located next to the inner nuclear membrane. The lamin family of proteins make up the matrix and are highly conserved in evolution. During mitosis, the lamina matrix is reversibly disassembled as the lamin proteins are phosphorylated. Lamin proteins are thought to be involved in nuclear stability, chromatin structure and gene expression. Vertebrate lamins consist of two types, A and B. Through alternate splicing, this gene encodes three type A lamin isoforms.[4]

Early in mitosis, MPF phosphorylates specific serine residues in all three nuclear lamins, causing depolymerization of the lamin intermediate filaments. The phosphorylated lamin B dimers remain associated with the nuclear membrane via their isoprenyl anchor. Lamin A is targeted to the nuclear membrane by an isoprenyl group but it is cleaved shortly after arriving at the membrane. It stays associated with the membrane through protein-protein interactions of itself and other membrane associated proteins, such as LAP1. Depolymerization of the nuclear lamins leads to disintegration of the nuclear envelope. Transfection experiments demonstrate that phosphorylation of human lamin A is required for lamin depolymerization, and thus for disassembly of the nuclear envelope, which normally occurs early in mitosis.

Clinical significance[edit]

Wild type (left) and mutated (right) form of lamin A (LMNA, PDB: 1IFR). Normally, arginine 527 (blue) forms salt bridge with glutamate 537 (magenta), but R527L substitution results in braking this interaction (leucine is to short to reach glutamate). Models are presented in surface (upper) and in cartoon representation (down).[5]

Mutations in the LMNA gene are associated with several diseases, including Emery-Dreifuss muscular dystrophy, familial partial lipodystrophy, limb girdle muscular dystrophy, dilated cardiomyopathy, Charcot-Marie-Tooth disease, Restrictive dermopathy and Hutchinson-Gilford progeria syndrome. A truncated version of lamin A, commonly known as progerin, causes Hutchinson-Gilford progeria syndrome.[6][7] To date over 1,400 SNPs are known [3]. They can manifest in changes on mRNA, splicing or protein (e.g. Arg471Cys,[8] Arg482Gln,[9] Arg527Leu,[10] Arg527Cys,[11] Ala529Val [12] ) level.


LMNA has been shown to interact with:


  1. ^ Kamat A, Rocchi M, Smith D, Miller O (March 1993). "Lamin A/C gene and a related sequence map to human chromosomes 1q12.1-q23 and 10". Somat. Cell Mol. Genet. 19 (2): 203–8. doi:10.1007/BF01233534. PMID 8511676. 
  2. ^ Wydner K, McNeil J, Lin F, Worman H, Lawrence J (March 1996). "Chromosomal assignment of human nuclear envelope protein genes LMNA, LMNB1, and LBR by fluorescence in situ hybridization". Genomics 32 (3): 474–8. doi:10.1006/geno.1996.0146. PMID 8838815. 
  3. ^ Coutinho HD, Falcão-Silva VS, Gonçalves GF, da Nóbrega RB; Falcão-Silva; Gonçalves; Da Nóbrega (2009). "Molecular ageing in progeroid syndromes: Hutchinson-Gilford progeria syndrome as a model". Immun Ageing 6: 4. doi:10.1186/1742-4933-6-4. PMC 2674425. PMID 19379495. 
  4. ^ "Entrez Gene: LMNA lamin A/C". 
  5. ^ Al-Haggar M, Madej-Pilarczyk A, Kozlowski L, Bujnicki J, Yahia S, Abdel-Hadi D et al. (2012). "A novel homozygous p.Arg527Leu LMNA mutation in two unrelated Egyptian families causes overlapping mandibuloacral dysplasia and progeria syndrome". Eur J Hum Genet. 20 (11): 1134–40. doi:10.1038/ejhg.2012.77. PMC 3476705. PMID 22549407. 
  6. ^ Capell B, Collins F (December 2006). "Human laminopathies: nuclei gone genetically awry". Nat. Rev. Genet. 7 (12): 940–52. doi:10.1038/nrg1906. PMID 17139325. 
  7. ^ Rankin J, Ellard S (October 2006). "The laminopathies: a clinical review". Clin. Genet. 70 (4): 261–74. doi:10.1111/j.1399-0004.2006.00677.x. PMID 16965317. 
  8. ^ Zirn B et al. (2008). "Association of homozygous LMNA mutation R471C with new phenotype: mandibuloacral dysplasia, progeria, and rigid spine muscular dystrophy". Am J Med Genet A 146A (8): 1049–1054. doi:10.1002/ajmg.a.32259. PMID 18348272. 
  9. ^ Cao H, Hegele R (2002). "Nuclear lamin A/C R482Q mutation in Canadian kindreds with Dunnigan-type familial partial lipodystrophy". Hum. Molec. Genet. 9 (1): 109–12. doi:10.1093/hmg/9.1.109. PMID 10587585. 
  10. ^ Al-Haggar M, Madej-Pilarczyk A, Kozlowski L, Bujnicki J, Yahia S, Abdel-Hadi D et al. (2012). "A novel homozygous p.Arg527Leu LMNA mutation in two unrelated Egyptian families causes overlapping mandibuloacral dysplasia and progeria syndrome". Eur J Hum Genet. 20 (11): 1134–40. doi:10.1038/ejhg.2012.77. PMC 3476705. PMID 22549407. 
  11. ^ Agarwal A, Kazachkova I, Ten S, Garg A (2008). "Severe mandibuloacral dysplasia-associated lipodystrophy and progeria in a young girl with a novel homozygous Arg527Cys LMNA mutation". J Clin Endocrinol Metab 93 (12): 4617–4623. doi:10.1210/jc.2008-0123. PMC 2626450. PMID 18796515. 
  12. ^ Garg A, Cogulu O, Ozkinay F, Onay H, Agarwal A (2005). "A novel homozygous Ala529Val LMNA mutation in Turkish patients with mandibuloacral dysplasia". J. Clin. Endocrinol. Metab. 90 (9): 5259–64. doi:10.1210/jc.2004-2560. PMID 15998779. 
  13. ^ Tang K, Finley R, Nie D, Honn K (March 2000). "Identification of 12-lipoxygenase interaction with cellular proteins by yeast two-hybrid screening". Biochemistry 39 (12): 3185–91. doi:10.1021/bi992664v. PMID 10727209. 
  14. ^ Wilkinson F, Holaska J, Zhang Z, Sharma A, Manilal S, Holt I et al. (June 2003). "Emerin interacts in vitro with the splicing-associated factor, YT521-B". Eur. J. Biochem. 270 (11): 2459–66. doi:10.1046/j.1432-1033.2003.03617.x. PMID 12755701. 
  15. ^ Lattanzi G, Cenni V, Marmiroli S, Capanni C, Mattioli E, Merlini L et al. (April 2003). "Association of emerin with nuclear and cytoplasmic actin is regulated in differentiating myoblasts". Biochem. Biophys. Res. Commun. 303 (3): 764–70. doi:10.1016/S0006-291X(03)00415-7. PMID 12670476. 
  16. ^ Sakaki M, Koike H, Takahashi N, Sasagawa N, Tomioka S, Arahata K et al. (February 2001). "Interaction between emerin and nuclear lamins". J. Biochem. 129 (2): 321–7. doi:10.1093/oxfordjournals.jbchem.a002860. PMID 11173535. 
  17. ^ Clements L, Manilal S, Love D, Morris G (January 2000). "Direct interaction between emerin and lamin A". Biochem. Biophys. Res. Commun. 267 (3): 709–14. doi:10.1006/bbrc.1999.2023. PMID 10673356. 
  18. ^ Barton R, Worman H (October 1999). "Prenylated prelamin A interacts with Narf, a novel nuclear protein". J. Biol. Chem. 274 (42): 30008–18. doi:10.1074/jbc.274.42.30008. PMID 10514485. 
  19. ^ Lloyd D, Trembath R, Shackleton S (April 2002). "A novel interaction between lamin A and SREBP1: implications for partial lipodystrophy and other laminopathies". Hum. Mol. Genet. 11 (7): 769–77. doi:10.1093/hmg/11.7.769. PMID 11929849. 
  20. ^ Markiewicz E, Dechat T, Foisner R, Quinlan R, Hutchison C (December 2002). "Lamin A/C binding protein LAP2alpha is required for nuclear anchorage of retinoblastoma protein". Mol. Biol. Cell 13 (12): 4401–13. doi:10.1091/mbc.E02-07-0450. PMC 138642. PMID 12475961. 
  21. ^ Dechat T, Korbei B, Vaughan O, Vlcek S, Hutchison C, Foisner R (October 2000). "Lamina-associated polypeptide 2alpha binds intranuclear A-type lamins". J. Cell. Sci. 113 (19): 3473–84. PMID 10984438. 
  22. ^ Dreuillet C, Tillit J, Kress M, Ernoult-Lange M (November 2002). "In vivo and in vitro interaction between human transcription factor MOK2 and nuclear lamin A/C". Nucleic Acids Res. 30 (21): 4634–42. doi:10.1093/nar/gkf587. PMC 135794. PMID 12409453. 
  23. ^ Liu B, Ghosh S, Yang X, Zheng H, Liu X, Wang Z et al. (2012). "Resveratrol Rescues SIRT1-Dependent Adult Stem Cell Decline and Alleviates Progeroid Features in Laminopathy-Based Progeria". Cell Metabolism 16 (6): 738–750. doi:10.1016/j.cmet.2012.11.007. PMID 23217256. 

Further reading[edit]

External links[edit]