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.^[9] They can manifest in changes on mRNA, splicing or protein (e.g. Arg471Cys,^[10] Arg482Gln,^[11] Arg527Leu, 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 . Journal of Structural Biology . 129 . 2–3 . 313–323 . April 2000 . 10806082 . 10.1006/jsbi.2000.4216 .
• Worman HJ, Courvalin JC . The inner nuclear membrane . The Journal of Membrane Biology . 177 . 1 . 1–11 . September 2000 . 10960149 . 10.1007/s002320001096 . 20121844 .
• Burke B, Mounkes LC, Stewart CL . The nuclear envelope in muscular dystrophy and cardiovascular diseases . Traffic . 2 . 10 . 675–683 . October 2001 . 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 in Cardiovascular Medicine . 11 . 7 . 280–285 . October 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] . Journal de la Société de Biologie . 195 . 3 . 249–257 . 2002 . 11833462 . 10.1051/jbio/2001195030249 . 70531120 .
• Helbling-Leclerc A, Bonne G, Schwartz K . Emery-Dreifuss muscular dystrophy . European Journal of Human Genetics . 10 . 3 . 157–161 . March 2002 . 11973618 . 10.1038/sj.ejhg.5200744 . free .
• Burke B, Stewart CL . Life at the edge: the nuclear envelope and human disease . Nature Reviews. Molecular Cell Biology . 3 . 8 . 575–585 . August 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 . 370–375 . September 2003 . 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] . it . Italian Heart Journal. Supplement . 5 . 2 . 98–111 . February 2004 . 15080529 . Diseases associated with lamin A/C gene defects: what the clinical cardiologist ought to know .
• Al-Shali KZ, Hegele RA . Laminopathies and atherosclerosis . Arteriosclerosis, Thrombosis, and Vascular Biology . 24 . 9 . 1591–1595 . September 2004 . 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 . The Journal of Clinical Endocrinology and Metabolism . 90 . 9 . 5259–5264 . September 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 . 5 . 2 . 286–289 . February 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 & Metabolism . 31 . 6 . 527–532 . December 2005 . 16357800 . 10.1016/S1262-3636(07)70227-6 .
• Young SG, Meta M, Yang SH, Fong LG . Prelamin A farnesylation and progeroid syndromes . The Journal of Biological Chemistry . 281 . 52 . 39741–39745 . December 2006 . 17090536 . 10.1074/jbc.R600033200 . free .
• Halaschek-Wiener J, Brooks-Wilson A . Progeria of stem cells: stem cell exhaustion in Hutchinson-Gilford progeria syndrome . The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences . 62 . 1 . 3–8 . January 2007 . 17301031 . 10.1093/gerona/62.1.3 . free .
• 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 . The British Journal of Dermatology . 156 . 6 . 1308–1314 . June 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] . Postepy Biochemii . 53 . 1 . 46–52 . 2007 . 17718387 .
• Genschel J, Schmidt HH . Mutations in the LMNA gene encoding lamin A/C . Human Mutation . 16 . 6 . 451–459 . 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 . Nature Medicine . 11 . 4 . 440–445 . April 2005 . 15750600 . 1351119 . 10.1038/nm1204 .
• Book: Bird TD . GeneReviews® . 1993 . University of Washington, Seattle . https://www.ncbi.nlm.nih.gov/books/NBK1285/ . Charcot-Marie-Tooth Neuropathy Type 2 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY . 20301462 .
• Book: Sparks SE, Quijano-Roy S, Harper A, Rutkowski A, Gordon E, Hoffman EP, Pegoraro E . GeneReviews® . 1993 . University of Washington, Seattle . https://www.ncbi.nlm.nih.gov/books/NBK1291/ . Congenital Muscular Dystrophy Overview – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY . 20301468 .
• Book: Hershberger RE, Jordan E . GeneReviews® . 1993 . University of Washington, Seattle . https://www.ncbi.nlm.nih.gov/books/NBK1674/ . LMNA-Related Dilated Cardiomyopathy . 20301717 .
• Book: Pegoraro E, Hoffman EP . GeneReviews® . 1993 . University of Washington, Seattle . https://www.ncbi.nlm.nih.gov/books/NBK1408/ . Limb-Girdle Muscular Dystrophy Overview – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY . 20301582 .
• Book: Bonne G, Leturcq F, Ben Yaou R . GeneReviews® . 1993 . University of Washington, Seattle . https://www.ncbi.nlm.nih.gov/books/NBK1436/ . Emery-Dreifuss Muscular Dystrophy . 20301609 .
• Book: Gordon LB, Brown WT, Collins FS . GeneReviews® . 1993 . University of Washington, Seattle . https://www.ncbi.nlm.nih.gov/books/NBK1121/ . Hutchinson-Gilford Progeria Syndrome . 20301300 .
• Book: Martín B, Smith RJ . GeneReviews® . 1993 . University of Washington, Seattle . https://www.ncbi.nlm.nih.gov/books/NBK1425/ . C3 Glomerulopathy . 20301598 .

External links

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

Notes and References

1. Lin F, Worman HJ . Structural organization of the human gene encoding nuclear lamin A and nuclear lamin C . The Journal of Biological Chemistry . 268 . 22 . 16321–16326 . August 1993 . 8344919 . 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 . Somatic Cell and Molecular Genetics . 19 . 2 . 203–208 . 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 . 474–478 . March 1996 . 8838815 . 10.1006/geno.1996.0146 . free .
4. Buxboim A, Swift J, Irianto J, Spinler KR, Dingal PC, Athirasala A, Kao YR, Cho S, Harada T, Shin JW, Discher DE . 6 . Matrix elasticity regulates lamin-A,C phosphorylation and turnover with feedback to actomyosin . Current Biology . 24 . 16 . 1909–1917 . August 2014 . 25127216 . 4373646 . 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 . Immunity & Ageing . 6 . 4 . April 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 . Nature Reviews. Genetics . 7 . 12 . 940–952 . December 2006 . 17139325 . 10.1038/nrg1906 . 13438737 .
8. Rankin J, Ellard S . The laminopathies: a clinical review . Clinical Genetics . 70 . 4 . 261–274 . October 2006 . 16965317 . 10.1111/j.1399-0004.2006.00677.x . 7234475 .
9. Web site: Variants for LMNA Gene .
10. Zirn B, Kress W, Grimm T, Berthold LD, Neubauer B, Kuchelmeister K, Müller U, Hahn A . 6 . Association of homozygous LMNA mutation R471C with new phenotype: mandibuloacral dysplasia, progeria, and rigid spine muscular dystrophy . American Journal of Medical Genetics. Part A . 146A . 8 . 1049–1054 . April 2008 . 18348272 . 10.1002/ajmg.a.32259 . 205309256 .
11. Cao H, Hegele RA . Nuclear lamin A/C R482Q mutation in canadian kindreds with Dunnigan-type familial partial lipodystrophy . Human Molecular Genetics . 9 . 1 . 109–112 . January 2000 . 10587585 . 10.1093/hmg/9.1.109 . free .
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 . The Journal of Clinical Endocrinology and Metabolism . 93 . 12 . 4617–4623 . December 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 . The Journal of Clinical Endocrinology and Metabolism . 90 . 9 . 5259–5264 . September 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 . 6 . A dual role for A-type lamins in DNA double-strand break repair . Cell Cycle . 10 . 15 . 2549–2560 . August 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 . Current Opinion in Cell Biology . 34 . 75–83 . June 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 . 6 . Genomic instability in laminopathy-based premature aging . Nature Medicine . 11 . 7 . 780–785 . July 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 . 3185–3191 . 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 . 6 . Emerin interacts in vitro with the splicing-associated factor, YT521-B . European Journal of Biochemistry . 270 . 11 . 2459–2466 . 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 . 6 . Association of emerin with nuclear and cytoplasmic actin is regulated in differentiating myoblasts . Biochemical and Biophysical Research Communications . 303 . 3 . 764–770 . 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 . Journal of Biochemistry . 129 . 2 . 321–327 . February 2001 . 11173535 . 10.1093/oxfordjournals.jbchem.a002860 . free .
21. Clements L, Manilal S, Love DR, Morris GE . Direct interaction between emerin and lamin A . Biochemical and Biophysical Research Communications . 267 . 3 . 709–714 . January 2000 . 10673356 . 10.1006/bbrc.1999.2023 .
22. Barton RM, Worman HJ . Prenylated prelamin A interacts with Narf, a novel nuclear protein . The Journal of Biological Chemistry . 274 . 42 . 30008–30018 . 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 . Human Molecular Genetics . 11 . 7 . 769–777 . 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 . Molecular Biology of the Cell . 13 . 12 . 4401–4413 . 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 . Journal of Cell Science . 113 . 19 . 3473–3484 . October 2000 . 10984438 . 10.1242/jcs.113.19.3473 .
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 Research . 30 . 21 . 4634–4642 . 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 . 6 . Resveratrol rescues SIRT1-dependent adult stem cell decline and alleviates progeroid features in laminopathy-based progeria . Cell Metabolism . 16 . 6 . 738–750 . December 2012 . 23217256 . 10.1016/j.cmet.2012.11.007 . free .