LMNA
Encyclopedia
Lamin A/C also known as LMNA is a protein
that in humans is encoded by the LMNA gene
. Lamin A/C belongs to the lamin
family of proteins.
consists 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.
, familial partial lipodystrophy
, limb girdle muscular dystrophy, dilated cardiomyopathy
, Charcot-Marie-Tooth disease
, and Hutchinson-Gilford progeria syndrome. A truncated version of lamin A, commonly known as progerin
, causes Hutchinson-Gilford progeria syndrome.
with:
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that in humans is encoded by the LMNA gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
. Lamin A/C belongs to the lamin
Lamin
Nuclear lamins, also known as Class V intermediate filaments, are fibrous proteins providing structural function and transcriptional regulation in the cell nucleus. Nuclear lamins interact with membrane-associated proteins to form the nuclear lamina on the interior of the nuclear envelope...
family of proteins.
Function
The nuclear laminaNuclear lamina
The nuclear lamina is a dense fibrillar network inside the nucleus of a eukaryotic cell. It is composed of intermediate filaments and membrane associated proteins. Besides providing mechanical support, the nuclear lamina regulates important cellular events such as DNA replication and cell division...
consists of a two-dimensional matrix of proteins located next to the inner nuclear membrane
Inner nuclear membrane proteins
Inner nuclear membrane proteins are proteins that are embedded in or associated with the inner membrane of the nuclear envelope. They have been postulated to function during NE formation at the conclusion of mitosis. Several INM proteins have been associated with transcriptional activity. Some INM...
. The lamin
Lamin
Nuclear lamins, also known as Class V intermediate filaments, are fibrous proteins providing structural function and transcriptional regulation in the cell nucleus. Nuclear lamins interact with membrane-associated proteins to form the nuclear lamina on the interior of the nuclear envelope...
family of proteins make up the matrix and are highly conserved in evolution. During mitosis
Mitosis
Mitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets, in two separate nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly...
, the lamina matrix is reversibly disassembled as the lamin proteins are phosphorylated
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
. Lamin proteins are thought to be involved in nuclear stability, chromatin
Chromatin
Chromatin is the combination of DNA and proteins that make up the contents of the nucleus of a cell. The primary functions of chromatin are; to package DNA into a smaller volume to fit in the cell, to strengthen the DNA to allow mitosis and meiosis and prevent DNA damage, and to control gene...
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
Prenylation
Prenylation, or isoprenylation, or lipidation is the addition of hydrophobic molecules to a protein. It is usually assumed that prenyl groups facilitate attachment to cell membranes, similar to lipid anchor like the GPI anchor, though direct evidence is missing...
. 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.
Clinical significance
Mutations in the LMNA gene are associated with several diseases, including Emery-Dreifuss muscular dystrophyEmery-Dreifuss muscular dystrophy
Emery–Dreifuss muscular dystrophy is a condition that chiefly affects muscles used for movement and heart muscle.It is named after Alan Eglin H. Emery and Fritz E. Dreifuss.-Presentation:...
, familial partial lipodystrophy
Familial partial lipodystrophy
Familial partial lipodystrophy is an autosomal dominant skin condition characterized by the loss of subcutaneous fat.Type 1 is believed to be underdiagnosed.- References :...
, limb girdle muscular dystrophy, dilated cardiomyopathy
Dilated cardiomyopathy
Dilated cardiomyopathy or DCM is a condition in which the heart becomes weakened and enlarged and cannot pump blood efficiently. The decreased heart function can affect the lungs, liver, and other body systems....
, Charcot-Marie-Tooth disease
Charcot-Marie-Tooth disease
Charcot–Marie–Tooth disease- , known also as Morbus Charcot-Marie-Tooth, Charcot-Marie-Tooth neuropathy, hereditary motor and sensory neuropathy , hereditary sensorimotor neuropathy , or peroneal muscular atrophy, is an inherited disorder of nerves that takes different forms...
, and Hutchinson-Gilford progeria syndrome. A truncated version of lamin A, commonly known as progerin
Progerin
Progerin is a truncated version of lamin A protein involved in Hutchinson-Gilford progeria syndrome. Progerin is most often generated by a silent point mutation in the lamin A gene, LMNA. This mutation activates a cryptic splice site and gives rise to a form of lamin A with a deletion of 50 amino...
, causes Hutchinson-Gilford progeria syndrome.
Interactions
LMNA has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with:
- ALOX12ALOX12Arachidonate 12-lipoxygenase, 12S-type is an enzyme that in humans is encoded by the ALOX12 gene.-Interactions:ALOX12 has been shown to interact with Keratin 5 and LMNA.-Further reading:...
, - EMDEmerinEmerin, together with MAN1, is a LEM domain-containing integral membrane protein of the nuclear membrane in vertebrates. The function of MAN1 is not extensively known, but emerin is known to interact with nuclear lamins, barrier-to-autointegration factor , nesprin-1α, and a transcription...
- NARFNARFNuclear prelamin A recognition factor, also known as NARF, is a protein which in humans is encoded by the NARF gene.-Function:Several proteins have been found to be prenylated and methylated at their carboxyl-terminal ends. Prenylation was initially believed to be important only for membrane...
, - SREBF1SREBF1Sterol regulatory element-binding transcription factor 1 also known as sterol regulatory element-binding protein 1 is a protein that in humans is encoded by the SREBF1 gene....
, - TMPOThymopoietinLamina-associated polypeptide 2, isoforms beta/gamma is a protein that in humans is encoded by the TMPO gene.Thymopoietin is a protein involved in the induction of CD90 in the thymus. The thymopoetin gene encodes three alternatively spliced mRNAs encoding proteins of 75 kDa , 51 kDa and 39 kDa ...
, and - ZNF239ZNF239Zinc finger protein 239 is a protein that in humans is encoded by the ZNF239 gene....
,
External links
- GeneReviews/NCBI/NIH/UW entry on Charcot-Marie-Tooth Neuropathy Type 2
- GeneReviews/NCBI/NIH/UW entry on Congenital Muscular Dystrophy Overview
- GeneReviews/NCBI/NIH/UW entry on LMNA-Related Dilated Cardiomyopathy
- OMIM entries on LMNA-Related Dilated Cardiomyopathy
- GeneReviews/NCBI/NIH/UW entry on Limb-Girdle Muscular Dystrophy Overview
- GeneReviews/NCBI/NIH/UW entry on Emery-Dreifuss Muscular Dystrophy
- GeneReviews/NCBI/NIH/UW entry on Hutchinson-Gilford Progeria Syndrome
- GeneReviews/NCBI/NIH/UW entry on Dense Deposit Disease/Membranoproliferative Glomerulonephritis Type II
- LOVD mutation database: LMNA