Prelamin-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 residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

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

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

. Lamin A/C belongs to the

lamin Lamins, also known as nuclear lamins, are fibrous proteins in Intermediate filament#Type V – nuclear lamins, type V intermediate filaments, providing structural function and Transcription (biology), transcriptional regulation in the cell nucle ...

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 ZMPSTE24 is a human gene. The protein encoded by this gene is a metallopeptidase. It is involved in the processing of lamin A. Defects in the ZMPSTE24 gene lead to similar laminopathies as defects in lamin A, because the latter is a su ...

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 The nuclear lamina is a dense (~30 to 100 nm thick) fibrillar network inside the nucleus of eukaryote cells. It is composed of intermediate filaments and membrane associated proteins. Besides providing mechanical support, the nuclear lam ...

consist of a two-dimensional matrix of proteins located next to the inner nuclear membrane. The

family of proteins make up the matrix and are highly conserved in evolution. During

mitosis Mitosis () is a part of the cell cycle in eukaryote, eukaryotic cells in which replicated chromosomes are separated into two new Cell nucleus, nuclei. Cell division by mitosis is an equational division which gives rise to genetically identic ...

, the lamina matrix is reversibly disassembled as the lamin proteins are

phosphorylated In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols: : This equation can be writt ...

. 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 r ...

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

alternate splicing Alternative splicing, alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to produce different splice variants. For example, some exons of a gene may be included ...

, this gene encodes three type A lamin isoforms. Early in mitosis,

maturation promoting factor Maturation-promoting factor (abbreviated MPF, also called mitosis-promoting factor or M-Phase-promoting factor) is the cyclin–Cdk complex that was discovered first in frog eggs. It stimulates the mitotic and meiotic phases of the cell cycle. ...

(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 Torsin-1A-interacting protein 1 is a protein that in humans is encoded by the ''TOR1AIP1'' gene. More commonly known as lamina associated polypeptide 1 (LAP1), it is a type II integral membrane protein that resides in the inner nuclear membrane. T ...

(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 des ...

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 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 contr ...

, familial partial lipodystrophy, limb girdle muscular dystrophy,

dilated cardiomyopathy Dilated cardiomyopathy (DCM) is a condition in which the heart becomes enlarged and cannot pump blood effectively. Symptoms vary from none to feeling tired, leg swelling, and shortness of breath. It may also result in chest pain or fainting. C ...

Charcot–Marie–Tooth disease Charcot-Marie-Tooth disease (CMT) is an inherited neurological disorder that affects the peripheral nerves responsible for transmitting signals between the brain, spinal cord, and the rest of the body. This is the most common inherited neuropath ...

, and restrictive dermopathy. A truncated version of lamin A, commonly known as

progerin Progerin (UniProt# P02545-6) is a truncated version of the lamin A protein involved in the pathology of Hutchinson–Gilford progeria syndrome. Progerin is most often generated by a sporadic single point nucleotide polymorphism c.1824 C>T (GGC -> ...

, causes Hutchinson-Gilford-Progeria syndrome. To date over 1,400

SNPs In genetics and bioinformatics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in ...

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 Cell (biology), cellular organi ...

(HR) or

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

(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 or Hutchinson–Gilford progeroid syndrome (HGPS). A single gene mutation is responsible for causing progeria. The affected gene, known as lamin A ( ...

, the inadequacy of DNA repair, due to defective LMNA, may cause features of premature aging (see

DNA damage theory of aging The DNA damage theory of aging proposes that aging is a consequence of unrepaired accumulation of DNA damage (naturally occurring), naturally occurring DNA damage. Damage in this context is a DNA alteration that has an abnormal structure. Although ...

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 Sterol regulatory element-binding transcription factor 1 (SREBF1) also known as sterol regulatory element-binding protein 1 (SREBP-1) is a protein that in humans is encoded by the ''SREBF1'' gene. This gene is located within the Smith–Magenis ...

* 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 fa ...

References

External links