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.
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.
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.
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, [16] Arg527Cys, [17] Ala529Val [18] ) level.
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. [19] [20] 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. [21] In progeria, the inadequacy of DNA repair, due to defective LMNA, may cause features of premature aging (see DNA damage theory of aging).
LMNA has been shown to interact with:
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 gene, known as lamin A (LMNA), makes a protein necessary for holding the nucleus of the cell together. When this gene gets mutated, an abnormal form of lamin A protein called progerin is produced. Progeroid syndromes are a group of diseases that causes individuals to age faster than usual, leading to them appearing older than they actually are. Patients born with progeria typically live to an age of mid-teens to early twenties.
Lamins, also known as nuclear lamins are fibrous proteins in type V intermediate filaments, providing structural function and transcriptional regulation in the cell nucleus. Nuclear lamins interact with inner nuclear membrane proteins to form the nuclear lamina on the interior of the nuclear envelope. Lamins have elastic and mechanosensitive properties, and can alter gene regulation in a feedback response to mechanical cues. Lamins are present in all animals but are not found in microorganisms, plants or fungi. Lamin proteins are involved in the disassembling and reforming of the nuclear envelope during mitosis, the positioning of nuclear pores, and programmed cell death. Mutations in lamin genes can result in several genetic laminopathies, which may be life-threatening.
In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution.
Malouf syndrome is a congenital disorder that causes one or more of the following symptoms: mental retardation, ovarian dysgenesis, congestive cardiomyopathy, broad nasal base, blepharoptosis, and bone abnormalities, and occasionally marfanoid habitus.
Congenital muscular dystrophies are autosomal recessively-inherited muscle diseases. They are a group of heterogeneous disorders characterized by muscle weakness which is present at birth and the different changes on muscle biopsy that ranges from myopathic to overtly dystrophic due to the age at which the biopsy takes place.
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, causing atrophy, weakness and contractures. It almost always affects the heart, causing abnormal rhythms, heart failure, or sudden cardiac death. It is rare, affecting 0.39 per 100,000 people. It is named after Alan Eglin H. Emery and Fritz E. Dreifuss.
Emerin is a protein that in humans is encoded by the EMD gene, also known as the STA gene. Emerin, together with LEMD3, is a LEM domain-containing integral protein of the inner nuclear membrane in vertebrates. Emerin is highly expressed in cardiac and skeletal muscle. In cardiac muscle, emerin localizes to adherens junctions within intercalated discs where it appears to function in mechanotransduction of cellular strain and in beta-catenin signaling. Mutations in emerin cause X-linked recessive Emery–Dreifuss muscular dystrophy, cardiac conduction abnormalities and dilated cardiomyopathy.
Laminopathies are a group of rare genetic disorders caused by mutations in genes encoding proteins of the nuclear lamina. They are included in the more generic term nuclear envelopathies that was coined in 2000 for diseases associated with defects of the nuclear envelope. Since the first reports of laminopathies in the late 1990s, increased research efforts have started to uncover the vital role of nuclear envelope proteins in cell and tissue integrity in animals.
Restrictive dermopathy (RD) is a rare, lethal autosomal recessive skin condition characterized by syndromic facies, tight skin, sparse or absent eyelashes, and secondary joint changes.
Polyadenylate-binding protein 2 (PABP-2) also known as polyadenylate-binding nuclear protein 1 (PABPN1) is a protein that in humans is encoded by the PABPN1 gene. PABN1 is a member of a larger family of poly(A)-binding proteins in the human genome.
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. The luminal domain of LAP1 interacts with Torsin A and is necessary for the ATPase activity of Torsin A. LAP1 plays a critical role in skeletal and heart muscle. Mutations in TOR1AIP1 have been linked to muscular dystrophy and cardiomyopathy. It's deletion from mouse hepatocytes leads to defected very-low density lipoprotein secretion and causes non-alcoholic fatty liver disease and non-alcoholic steatohepatitis
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 substrate for the former. In humans, a mutation abolishing the ZMPSTE24 cleavage site in prelamin A causes a progeroid disorder. Failure to correctly process prelamin A leads to deficient ability to repair DNA double-strand breaks.
Progerin 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 in the gene that codes for matured Lamin A. This mutation activates a cryptic splice site that induces a mutation in premature Lamin A with the deletion of a 50 amino acids group near the C-terminus. The endopeptidase ZMPSTE24 cannot cleave between the missing RSY - LLG amino acid sequence during the maturation of Lamin A, due to the deletion of the 50 amino acids which included that sequence. This leaves the intact premature Lamin A bonded to the methylated carboxyl farnesyl group creating the defective protein Progerin, rather than the desired protein matured Lamin A. Approximately 90% of all Hutchinson–Gilford progeria syndrome cases are heterozygous for this deleterious single nucleotide polymorphism within exon 11 of the LMNA gene causing the post-translational modifications to produce Progerin.
In molecular biology, the CLP protease family is a family of serine peptidases belong to the MEROPS peptidase family S14. ClpP is an ATP-dependent protease that cleaves a number of proteins, such as casein and albumin. It exists as a heterodimer of ATP-binding regulatory A and catalytic P subunits, both of which are required for effective levels of protease activity in the presence of ATP, although the P subunit alone does possess some catalytic activity.
Progeroid syndromes (PS) are a group of rare genetic disorders that mimic physiological aging, making affected individuals appear to be older than they are. The term progeroid syndrome does not necessarily imply progeria, which is a specific type of progeroid syndrome.
Veena Krishnaji Parnaik is an Indian cell biologist and the current Chief Scientist at the Centre for Cellular and Molecular Biology. She obtained her Masters in Science in medicinal biochemistry from the University of Mumbai and received her PhD from Ohio State University before moving back to India to work at the CCMB. Her research is focused on understanding the functional role of the nuclear lamina and how defects in it may lead to disorders such as progeria and muscular dystrophy.
Lamin A/C congenital muscular dystrophy (CMD) is a disease that it is included in laminopathies. Laminopathies are caused, among other mutations, to mutations in LMNA, a gene that synthesizes lamins A and C.
Anoctamin 5 (ANO5) is a protein that in humans is encoded by the ANO5 gene.
Calpainopathy is the most common type of autosomal recessive limb-girdle muscular dystrophy (LGMD). It preferentially affects the muscles of the hip girdle and shoulder girdle.
Dystrophinopathy refers to a spectrum of diseases due to mutations in the DMD gene, which encodes for the dystrophin protein found in muscle. The severe end of the spectrum includes Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), and DMD-associated dilated cardiomyopathy. The mild end of the spectrum includes asymptomatic increases in serum creatine kinase and muscle cramps with myoglobinuria. Because dystrophin is located on the X chromosome, dystrophinopathy mainly affects males, whereas females range from being carriers, to having delayed-onset and mild disease, to having severe DMD.
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