Pre-lamin A/C or lamin A/C is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respon ...

that in humans is encoded by the ''LMNA''

gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

. Lamin A/C belongs to the lamin family of proteins.

Function

Biogenesis of lamin A in normal cells and the failure to generate mature lamin A in HGPS

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 In cell biology, mitosis () is a part of the cell cycle in which replicated chromosomes are separated into two new nuclei. Cell division by mitosis gives rise to genetically identical cells in which the total number of chromosomes is maint ...

, the lamina matrix is reversibly disassembled as the lamin proteins are phosphorylated. Lamin proteins are thought to be involved in nuclear stability,

chromatin Chromatin is a complex of DNA and protein found in eukaryote, eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important ...

structure and gene expression. Vertebrate lamins consist of two types, A and B. Through

alternate splicing Alternative splicing, or alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to code for multiple proteins. In this process, particular exons of a gene may be i ...

, this gene encodes three type A lamin isoforms. 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 Transfection is the process of deliberately introducing naked or purified nucleic acids into eukaryotic cells. It may also refer to other methods and cell types, although other terms are often preferred: " transformation" is typically used to de ...

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

LMNA protein (1ifr) mutation R527L PMID 22549407 surface and cartoon

Mutations in the ''LMNA'' gene are associated with several diseases, including

Emery–Dreifuss muscular dystrophy Emery–Dreifuss muscular dystrophy (EDMD) is a type of muscular dystrophy, a group of heritable diseases that cause progressive impairment of muscles. EDMD affects muscles used for movement ( skeletal muscles), causing atrophy, weakness and con ...

familial partial lipodystrophy Familial partial lipodystrophy, also known as Köbberling–Dunnigan syndrome, is a rare genetic metabolic condition characterized by the loss of subcutaneous fat. FPL also refers to a rare metabolic condition in which there is a loss of subcutane ...

, 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. To date over 1,400 SNPs are know

They can manifest in changes on mRNA, splicing or protein (e.g. Arg471Cys, Arg482Gln, Arg527Leu, Arg527Cys, Ala529Val ) level.

DNA damage

DNA damage (naturally occurring), DNA double-strand damages can be repaired by either

homologous recombination Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids (usually DNA as in cellular organisms but may be ...

(HR) or

non-homologous end joining Non-homologous end joining (NHEJ) is a pathway that repairs double-strand breaks in DNA. NHEJ is referred to as "non-homologous" because the break ends are directly ligated without the need for a homologous template, in contrast to homology direct ...

(NHEJ). LMNA promotes genetic stability by maintaining the levels of proteins that have key roles in HR and NHEJ. 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. In

progeria Progeria is a specific type of progeroid syndrome, also known as Hutchinson–Gilford syndrome. A single gene mutation is responsible for progeria. The gene, known as lamin A (LMNA), makes a protein necessary for holding the Nucleus of the cell ...

, 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 ALOX12 (), also known as arachidonate 12-lipoxygenase, 12-lipoxygenase, 12''S''-Lipoxygenase, 12-LOX, and 12''S''-LOX is a lipoxygenase-type enzyme that in humans is encoded by the ''ALOX12'' gene which is located along with other lipoyxgenases on ...

* EMD * NARF * SREBF1 * TMPO * ZNF239 *

SIRT1 Sirtuin 1, also known as NAD-dependent deacetylase sirtuin-1, is a protein that in humans is encoded by the SIRT1 gene. SIRT1 stands for sirtuin (silent mating type information regulation 2 homolog) 1 ('' S. cerevisiae''), referring to the fact ...

References

External links