Prelamin-A/C

Prelamin-A/C, or lamin A/C is a protein that in humans is encoded by the LMNA gene.^[5][6][7] Lamin A/C belongs to the lamin family of proteins.

LMNA
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1IFR, 1IVT, 1X8Y, 2XV5, 2YPT, 3GEF, 3V4Q, 3V4W, 3V5B
Identifiers
Aliases	LMNA, CDCD1, CDDC, CMD1A, CMT2B1, EMD2, FPL, FPLD, FPLD2, HGPS, IDC, LDP1, LFP, LGMD1B, LMN1, LMNC, LMNL1, PRO1, lamin A/C, MADA, A-type lamin
External IDs	OMIM: 150330; MGI: 96794; HomoloGene: 41321; GeneCards: LMNA; OMA:LMNA - orthologs
Gene location (Human) Chr. Chromosome 1 (human)[1] Band 1q22 Start 156,082,573 bp[1] End 156,140,081 bp[1]
Gene location (Mouse) Chr. Chromosome 3 (mouse)[2] Band 3 F1|3 38.84 cM Start 88,387,454 bp[2] End 88,417,263 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in nipple gastric mucosa skin of abdomen tendon of biceps brachii gallbladder skin of leg Descending thoracic aorta stromal cell of endometrium Achilles tendon left uterine tube Top expressed in ascending aorta aortic valve external carotid artery internal carotid artery endothelial cell of lymphatic vessel lip condyle skin of back skin of external ear lactiferous gland More reference expression data BioGPS More reference expression data
Gene ontology Molecular function structural molecule activity protein binding identical protein binding Cellular component nuclear lamina cytosol nuclear speck lamin filament perinuclear region of cytoplasm intermediate filament nucleus extracellular matrix nuclear membrane nucleoplasm nuclear envelope Biological process regulation of cell migration nucleus organization establishment or maintenance of microtubule cytoskeleton polarity negative regulation of release of cytochrome c from mitochondria negative regulation of extrinsic apoptotic signaling pathway muscle organ development regulation of protein localization to nucleus IRE1-mediated unfolded protein response mitotic nuclear membrane disassembly protein localization to nucleus mitotic nuclear membrane reassembly ventricular cardiac muscle cell development cellular response to hypoxia positive regulation of gene expression negative regulation of mesenchymal cell proliferation nuclear envelope organization negative regulation of cell population proliferation regulation of telomere maintenance negative regulation of cardiac muscle hypertrophy in response to stress protein import into nucleus regulation of protein stability positive regulation of histone H3-K9 trimethylation Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 4000 16905 Ensembl ENSG00000160789 ENSMUSG00000028063 UniProt P02545 P48678 RefSeq (mRNA) NM_001257374 NM_001282624 NM_001282625 NM_001282626 NM_005572 NM_170707 NM_170708 NM_001002011 NM_001111102 NM_019390 RefSeq (protein) NP_001244303 NP_001269553 NP_001269554 NP_001269555 NP_005563 NP_733821 NP_733822 NP_001002011 NP_001104572 NP_062263 Location (UCSC) Chr 1: 156.08 – 156.14 Mb Chr 3: 88.39 – 88.42 Mb PubMed search [3] [4]
Wikidata
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Function

Biogenesis of lamin A in normal cells and the failure to generate mature lamin A in Hutchinson–Gilford progeria syndrome.

^[8]

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.^[9] 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.^[10]

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

Wild type (left) and mutated (right) form of the Ig-fold of lamin A (LMNA, PDB: 1IFR). Normally, arginine 527 (blue) forms a salt bridge with glutamate 537 (magenta), but R527L substitution results in breaking this interaction (leucine is too short to reach glutamate). Models are presented in surface (upper) and in cartoon (lower) representation.^[11]

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.^[12][13] To date over 1,400 SNPs are known . They can manifest in changes on mRNA, splicing or protein (e.g. Arg471Cys,^[14] Arg482Gln,^[15] Arg527Leu,^[11] Arg527Cys,^[16] Ala529Val ^[17] ) 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.^[18][19] 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.^[20] 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^[21]
• EMD^{[22][23][24][25]}
• NARF^[26]
• SREBF1^[27]
• TMPO^[28][29]
• ZNF239^[30]
• SIRT1^[31]