Prelamin-A/C Explained

Prelamin-A/C, or lamin A/C is a protein that in humans is encoded by the LMNA gene.^{[1] [2] [3]} Lamin A/C belongs to the lamin family of proteins.

Function

^[4]

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.^[5] 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.^[6]

Early in mitosis, maturation promoting factor (abbreviated MPF, also called mitosis-promoting factor or M-phase-promoting factor) 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 TOR1AIP1 (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

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, and restrictive dermopathy. A truncated version of lamin A, commonly known as progerin, causes Hutchinson-Gilford-Progeria syndrome.^{[7] [8]} To date over 1,400 SNPs are known https://www.genecards.org/cgi-bin/carddisp.pl?gene=LMNA&#snp. They can manifest in changes on mRNA, splicing or protein (e.g. Arg471Cys,^[9] Arg482Gln,^[10] Arg527Leu,^[11] Arg527Cys,^[12] Ala529Val ^[13]) level.

DNA damage

DNA double-strand damages can be repaired by either homologous recombination (HR) or non-homologous end joining (NHEJ). LMNA promotes genetic stability by maintaining the levels of proteins that have key roles in HR and NHEJ.^{[14] [15]} Mouse cells that are deficient for maturation of prelamin A have increased DNA damage and chromosome aberrations, and show increased sensitivity to DNA damaging agents.^[16] In progeria, the inadequacy of DNA repair, due to defective LMNA, may cause features of premature aging (see DNA damage theory of aging).

Interactions

LMNA has been shown to interact with:

• ALOX12^[17]
• EMD^{[18] [19] [20] [21]}
• NARF^[22]
• SREBF1^[23]
• TMPO^{[24] [25]}
• ZNF239^[26]
• SIRT1^[27]

Further reading

• Gruenbaum Y, Wilson KL, Harel A, Goldberg M, Cohen M . Review: nuclear lamins--structural proteins with fundamental functions . J. Struct. Biol. . 129 . 2–3 . 313–23 . 2000 . 10806082 . 10.1006/jsbi.2000.4216 .
• Worman HJ, Courvalin JC . The inner nuclear membrane . J. Membr. Biol. . 177 . 1 . 1–11 . 2000 . 10960149 . 10.1007/s002320001096 . 20121844 .
• Burke B, Mounkes LC, Stewart CL . The nuclear envelope in muscular dystrophy and cardiovascular diseases . Traffic . 2 . 10 . 675–83 . 2002 . 11576443 . 10.1034/j.1600-0854.2001.21001.x . 19392394 . free .
• Mounkes LC, Burke B, Stewart CL . The A-type lamins: nuclear structural proteins as a focus for muscular dystrophy and cardiovascular diseases . Trends Cardiovasc. Med. . 11 . 7 . 280–5 . 2001 . 11709282 . 10.1016/S1050-1738(01)00126-8 .
• Vigouroux C, Magré J, Desbois-Mouthon C, Lascols O, Cherqui G, Caron M, Capeau J . [Major insulin resistance syndromes: clinical and physiopathological aspects] . J. Soc. Biol. . 195 . 3 . 249–57 . 2002 . 11833462 . 10.1051/jbio/2001195030249. 70531120 .
• Helbling-Leclerc A, Bonne G, Schwartz K . Emery–Dreifuss muscular dystrophy . Eur. J. Hum. Genet. . 10 . 3 . 157–61 . 2002 . 11973618 . 10.1038/sj.ejhg.5200744 . free .
• Burke B, Stewart CL . Life at the edge: the nuclear envelope and human disease . Nat. Rev. Mol. Cell Biol. . 3 . 8 . 575–85 . 2002 . 12154369 . 10.1038/nrm879 . 11913118 .
• Novelli G, D'Apice MR . The strange case of the "lumper" lamin A/C gene and human premature ageing . Trends in Molecular Medicine . 9 . 9 . 370–5 . 2004 . 13129702 . 10.1016/S1471-4914(03)00162-X .
• Pasotti M, Repetto A, Pisani A, Arbustini E . [Diseases associated with lamin A/C gene defects: what the clinical cardiologist ought to know] . Italian Heart Journal Supplement . 5 . 2 . 98–111 . 2004 . 15080529 .
• Al-Shali KZ, Hegele RA . Laminopathies and atherosclerosis . Arterioscler. Thromb. Vasc. Biol. . 24 . 9 . 1591–5 . 2005 . 15205220 . 10.1161/01.ATV.0000136392.59656.8b . free .
• Garg A, Cogulu O, Ozkinay F, Onay H, Agarwal AK . A novel homozygous Ala529Val LMNA mutation in Turkish patients with mandibuloacral dysplasia . J. Clin. Endocrinol. Metab. . 90 . 9 . 5259–64 . 2005 . 15998779 . 10.1210/jc.2004-2560 . free .
• Lees-Miller SP . Dysfunction of lamin A triggers a DNA damage response and cellular senescence . DNA Repair (Amst.) . 5 . 2 . 286–9 . 2006 . 16344005 . 10.1016/j.dnarep.2005.10.007 .
• Donadille B, Lascols O, Capeau J, Vigouroux C . Etiological investigations in apparent type 2 diabetes: when to search for lamin A/C mutations? . Diabetes Metab. . 31 . 6 . 527–32 . 2006 . 16357800 . 10.1016/S1262-3636(07)70227-6 .
• Young SG, Meta M, Yang SH, Fong LG . Prelamin A farnesylation and progeroid syndromes . J. Biol. Chem. . 281 . 52 . 39741–5 . 2007 . 17090536 . 10.1074/jbc.R600033200 . free .
• Halaschek-Wiener J, Brooks-Wilson A . Progeria of stem cells: stem cell exhaustion in Hutchinson–Gilford progeria syndrome . J. Gerontol. A Biol. Sci. Med. Sci. . 62 . 1 . 3–8 . 2007 . 17301031 . 10.1093/gerona/62.1.3 . free . 2019-08-15 . 2012-11-05 . https://web.archive.org/web/20121105123031/http://www.bcgsc.ca/project/healthy-aging-study/recent-publications/Halaschek-Wiener%20et%20al.%202007_Progeria.pdf . dead .
• Mazereeuw-Hautier J, Wilson LC, Mohammed S, Smallwood D, Shackleton S, Atherton DJ, Harper JI . Hutchinson–Gilford progeria syndrome: clinical findings in three patients carrying the G608G mutation in LMNA and review of the literature . Br. J. Dermatol. . 156 . 6 . 1308–14 . 2007 . 17459035 . 10.1111/j.1365-2133.2007.07897.x . 25944330 .
• Sliwińska MA . [The role of lamins and mutations of LMNA gene in physiological and premature aging] Polish . Postepy Biochem. . 53 . 1 . 46–52 . 2007 . 17718387 .
• Genschel J, Schmidt HH . Mutations in the LMNA gene encoding lamin A/C . Hum. Mutat. . 16 . 6 . 451–9 . December 2000 . 11102973 . 10.1002/1098-1004(200012)16:6<451::AID-HUMU1>3.0.CO;2-9 . 19320913 .
• Scaffidi P, Misteli T . Reversal of the cellular phenotype in the premature aging disease Hutchinson–Gilford progeria syndrome . Nat. Med. . 11 . 4 . 440–5 . April 2005 . 15750600 . 1351119 . 10.1038/nm1204 .
• Charcot–Marie–Tooth Neuropathy Type 2 . 1993 . 20301462 . Bird . T. D. . Adam . M. P. . Ardinger . H. H. . Pagon . R. A. . Wallace . S. E. . Bean LJH . Stephens . K. . Amemiya . A. .
• Congenital Muscular Dystrophy Overview . 1993 . 20301468 . Sparks . S. E. . Quijano-Roy . S. . Harper . A. . Rutkowski . A. . Gordon . E. . Hoffman . E. P. . Pegoraro . E. . Adam . M. P. . Ardinger . H. H. . Pagon . R. A. . Wallace . S. E. . Bean LJH . Stephens . K. . Amemiya . A. .
• LMNA-Related Dilated Cardiomyopathy . 1993 . 20301717 . Hershberger . R. E. . Morales . A. . Adam . M. P. . Ardinger . H. H. . Pagon . R. A. . Wallace . S. E. . Bean LJH . Stephens . K. . Amemiya . A. .
• Limb-Girdle Muscular Dystrophy Overview . 1993 . 20301582 . Pegoraro . E. . Hoffman . E. P. . Adam . M. P. . Ardinger . H. H. . Pagon . R. A. . Wallace . S. E. . Bean LJH . Stephens . K. . Amemiya . A. .
• Emery–Dreifuss Muscular Dystrophy . 1993 . 20301609 . Bonne . G. . Leturcq . F. . Ben Yaou . R. . Adam . M. P. . Ardinger . H. H. . Pagon . R. A. . Wallace . S. E. . Bean LJH . Stephens . K. . Amemiya . A. .
• Hutchinson–Gilford Progeria Syndrome . 1993 . 20301300 . Gordon . L. B. . Brown . W. T. . Collins . F. S. . Adam . M. P. . Ardinger . H. H. . Pagon . R. A. . Wallace . S. E. . Bean LJH . Stephens . K. . Amemiya . A. .
• Dense Deposit Disease/Membranoproliferative Glomerulonephritis Type II . 1993 . 20301598 . Martín . B. . Smith RJH . Adam . M. P. . Ardinger . H. H. . Pagon . R. A. . Wallace . S. E. . Bean LJH . Stephens . K. . Amemiya . A. .

External links

• • • • LOVD mutation database: LMNA
• GeneCards for LMNA
• Laminopathy Information Site for Lay Public

Notes and References

1. 8344919 . 268 . Structural organization of the human gene encoding nuclear lamin A and nuclear lamin C . 1993 . J Biol Chem . 16321–16326 . Lin F, Worman HJ . 22 . 10.1016/S0021-9258(19)85424-8 . free .
2. Kamat AK, Rocchi M, Smith DI, Miller OJ . 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 . March 1993 . 8511676 . 10.1007/BF01233534 . 32913788 .
3. Wydner KL, McNeil JA, Lin F, Worman HJ, Lawrence JB . Chromosomal assignment of human nuclear envelope protein genes LMNA, LMNB1, and LBR by fluorescence in situ hybridization . Genomics . 32 . 3 . 474–8 . March 1996 . 8838815 . 10.1006/geno.1996.0146 . free .
4. 25127216. 4373646. 2014. Buxboim. A.. Matrix elasticity regulates lamin-A,C phosphorylation and turnover with feedback to actomyosin. Current Biology. 24. 16. 1909–17. Swift. J.. Irianto. J.. Spinler. K. R.. Dingal. P. C.. Athirasala. A.. Kao. Y. R.. Cho. S.. Harada. T.. Shin. J. W.. Discher. D. E.. 10.1016/j.cub.2014.07.001. 2014CBio...24.1909B .
5. Coutinho HD, Falcão-Silva VS, Gonçalves GF, da Nóbrega RB . Molecular ageing in progeroid syndromes: Hutchinson–Gilford progeria syndrome as a model . Immun Ageing . 6 . 4 . 2009 . 19379495 . 2674425 . 10.1186/1742-4933-6-4 . free .
6. Web site: Entrez Gene: LMNA lamin A/C.
7. Capell BC, Collins FS . Human laminopathies: nuclei gone genetically awry . Nat. Rev. Genet. . 7 . 12 . 940–52 . December 2006 . 17139325 . 10.1038/nrg1906 . 13438737 .
8. Rankin J, Ellard S . The laminopathies: a clinical review . Clin. Genet. . 70 . 4 . 261–74 . October 2006 . 16965317 . 10.1111/j.1399-0004.2006.00677.x . 7234475 .
9. Zirn B, Kress W, Grimm T, Berthold LD, Neubauer B, Kuchelmeister K, Müller U, Hahn A . 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 . 2008 . 18348272 . 10.1002/ajmg.a.32259 . 205309256 .
10. Cao H, Hegele RA . Nuclear lamin A/C R482Q mutation in Canadian kindreds with Dunnigan-type familial partial lipodystrophy . Hum. Mol. Genet. . 9 . 1 . 109–12 . 2002 . 10587585 . 10.1093/hmg/9.1.109 . free .
11. Al-Haggar M, Madej-Pilarczyk A, Kozlowski L, Bujnicki JM, Yahia S, Abdel-Hadi D, Shams A, Ahmad N, Hamed S, Puzianowska-Kuznicka M . 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 . 2012 . 22549407 . 3476705 . 10.1038/ejhg.2012.77 .
12. Agarwal AK, Kazachkova I, Ten S, Garg A . 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 . 2008 . 18796515 . 2626450 . 10.1210/jc.2008-0123 .
13. Garg A, Cogulu O, Ozkinay F, Onay H, Agarwal AK . A novel homozygous Ala529Val LMNA mutation in Turkish patients with mandibuloacral dysplasia . J. Clin. Endocrinol. Metab. . 90 . 9 . 5259–64 . 2005 . 15998779 . 10.1210/jc.2004-2560 . free .
14. Redwood AB, Perkins SM, Vanderwaal RP, Feng Z, Biehl KJ, Gonzalez-Suarez I, Morgado-Palacin L, Shi W, Sage J, Roti-Roti JL, Stewart CL, Zhang J, Gonzalo S . A dual role for A-type lamins in DNA double-strand break repair . Cell Cycle . 10 . 15 . 2549–60 . 2011 . 21701264 . 3180193 . 10.4161/cc.10.15.16531 .
15. Gonzalo S, Kreienkamp R . DNA repair defects and genome instability in Hutchinson-Gilford Progeria Syndrome . Curr. Opin. Cell Biol. . 34 . 75–83 . 2015 . 26079711 . 4522337 . 10.1016/j.ceb.2015.05.007 .
16. Liu B, Wang J, Chan KM, Tjia WM, Deng W, Guan X, Huang JD, Li KM, Chau PY, Chen DJ, Pei D, Pendas AM, Cadiñanos J, López-Otín C, Tse HF, Hutchison C, Chen J, Cao Y, Cheah KS, Tryggvason K, Zhou Z . Genomic instability in laminopathy-based premature aging . Nat. Med. . 11 . 7 . 780–5 . 2005 . 15980864 . 10.1038/nm1266 . 11798376 .
17. Tang K, Finley RL, Nie D, Honn KV . Identification of 12-lipoxygenase interaction with cellular proteins by yeast two-hybrid screening . Biochemistry . 39 . 12 . 3185–91 . March 2000 . 10727209 . 10.1021/bi992664v .
18. Wilkinson FL, Holaska JM, Zhang Z, Sharma A, Manilal S, Holt I, Stamm S, Wilson KL, Morris GE . Emerin interacts in vitro with the splicing-associated factor, YT521-B . Eur. J. Biochem. . 270 . 11 . 2459–66 . June 2003 . 12755701 . 10.1046/j.1432-1033.2003.03617.x . 5963743 . free .
19. Lattanzi G, Cenni V, Marmiroli S, Capanni C, Mattioli E, Merlini L, Squarzoni S, Maraldi NM . Association of emerin with nuclear and cytoplasmic actin is regulated in differentiating myoblasts . Biochem. Biophys. Res. Commun. . 303 . 3 . 764–70 . April 2003 . 12670476 . 10.1016/S0006-291X(03)00415-7 .
20. Sakaki M, Koike H, Takahashi N, Sasagawa N, Tomioka S, Arahata K, Ishiura S . Interaction between emerin and nuclear lamins . J. Biochem. . 129 . 2 . 321–7 . February 2001 . 11173535 . 10.1093/oxfordjournals.jbchem.a002860 .
21. Clements L, Manilal S, Love DR, Morris GE . Direct interaction between emerin and lamin A . Biochem. Biophys. Res. Commun. . 267 . 3 . 709–14 . January 2000 . 10673356 . 10.1006/bbrc.1999.2023 .
22. Barton RM, Worman HJ . Prenylated prelamin A interacts with Narf, a novel nuclear protein . J. Biol. Chem. . 274 . 42 . 30008–18 . October 1999 . 10514485 . 10.1074/jbc.274.42.30008 . free .
23. Lloyd DJ, Trembath RC, Shackleton S . A novel interaction between lamin A and SREBP1: implications for partial lipodystrophy and other laminopathies . Hum. Mol. Genet. . 11 . 7 . 769–77 . April 2002 . 11929849 . 10.1093/hmg/11.7.769 . free .
24. Markiewicz E, Dechat T, Foisner R, Quinlan RA, Hutchison CJ . Lamin A/C binding protein LAP2alpha is required for nuclear anchorage of retinoblastoma protein . Mol. Biol. Cell . 13 . 12 . 4401–13 . December 2002 . 12475961 . 138642 . 10.1091/mbc.E02-07-0450 .
25. Dechat T, Korbei B, Vaughan OA, Vlcek S, Hutchison CJ, Foisner R . Lamina-associated polypeptide 2alpha binds intranuclear A-type lamins . J. Cell Sci. . 113 . 19 . 3473–84 . October 2000 . 10.1242/jcs.113.19.3473 . 10984438 .
26. Dreuillet C, Tillit J, Kress M, Ernoult-Lange M . In vivo and in vitro interaction between human transcription factor MOK2 and nuclear lamin A/C . Nucleic Acids Res. . 30 . 21 . 4634–42 . November 2002 . 12409453 . 135794 . 10.1093/nar/gkf587 .
27. Liu B, Ghosh S, Yang X, Zheng H, Liu X, Wang Z, Jin G, Zheng B, Kennedy BK, Suh Y, Kaeberlein M, Tryggvason K, Zhou Z . Resveratrol Rescues SIRT1-Dependent Adult Stem Cell Decline and Alleviates Progeroid Features in Laminopathy-Based Progeria . Cell Metabolism . 16 . 6 . 738–750 . 2012 . 23217256 . 10.1016/j.cmet.2012.11.007 . free .