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.
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.
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.
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).
^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. PMID8511676.
^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". Genomics32 (3): 474–8. doi:10.1006/geno.1996.0146. PMID8838815.
^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 A146A (8): 1049–1054. doi:10.1002/ajmg.a.32259. PMID18348272.
^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. PMID10587585.
^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. PMID15998779.
^Tang K, Finley R, Nie D, Honn K (March 2000). "Identification of 12-lipoxygenase interaction with cellular proteins by yeast two-hybrid screening". Biochemistry39 (12): 3185–91. doi:10.1021/bi992664v. PMID10727209.
^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. PMID12755701.
^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. PMID12670476.
^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. PMID11929849.
^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 Metabolism16 (6): 738–750. doi:10.1016/j.cmet.2012.11.007. PMID23217256.
Gruenbaum Y, Wilson K, Harel A, Goldberg M, Cohen M (2000). "Review: nuclear lamins--structural proteins with fundamental functions". J. Struct. Biol.129 (2–3): 313–23. doi:10.1006/jsbi.2000.4216. PMID10806082.
Mounkes L, Burke B, Stewart C (2001). "The A-type lamins: nuclear structural proteins as a focus for muscular dystrophy and cardiovascular diseases". Trends Cardiovasc. Med.11 (7): 280–5. doi:10.1016/S1050-1738(01)00126-8. PMID11709282.
Vigouroux C, Magré J, Desbois-Mouthon C, Lascols O, Cherqui G, Caron M et al. (2002). "[Major insulin resistance syndromes: clinical and physiopathological aspects]". J. Soc. Biol.195 (3): 249–57. PMID11833462.
Pasotti M, Repetto A, Pisani A, Arbustini E (2004). "[Diseases associated with lamin A/C gene defects: what the clinical cardiologist ought to know]". Italian heart journal. Supplement : official journal of the Italian Federation of Cardiology5 (2): 98–111. PMID15080529.
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. PMID15998779.
Donadille B, Lascols O, Capeau J, Vigouroux C (2006). "Etiological investigations in apparent type 2 diabetes: when to search for lamin A/C mutations?". Diabetes Metab.31 (6): 527–32. doi:10.1016/S1262-3636(07)70227-6. PMID16357800.
Halaschek-Wiener J, Brooks-Wilson A (2007). "Progeria of stem cells: stem cell exhaustion in Hutchinson-Gilford progeria syndrome". J. Gerontol. A Biol. Sci. Med. Sci.62 (1): 3–8. doi:10.1093/gerona/62.1.3. PMID17301031.
Mazereeuw-Hautier J, Wilson L, Mohammed S, Smallwood D, Shackleton S, Atherton D et al. (2007). "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. doi:10.1111/j.1365-2133.2007.07897.x. PMID17459035.
Sliwińska M (2007). "[The role of lamins and mutations of LMNA gene in physiological and premature aging] Polish". Postepy Biochem.53 (1): 46–52. PMID17718387.