Progerin (UniProt# P02545-6) is a truncated version of the

lamin A Pre-lamin A/C or lamin A/C is a protein that in humans is encoded by the ''LMNA'' gene. Lamin A/C belongs to the lamin family of proteins. Function In the setting of ZMPSTE24 deficiency, the final step of lamin processing does not occur, res ...

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, respo ...

involved in the pathology of

Hutchinson–Gilford progeria syndrome 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 ...

. Progerin is most often generated by a sporadic single point nucleotide polymorphism c.1824 C>T (GGC -> GGT, p.Gly608Gly) in the gene that codes for matured Lamin A. This mutation activates a

cryptic splice site Cryptic may refer to: In science: * Cryptic species complex, a group of species that are very difficult to distinguish from one another * Crypsis, the ability of animals to blend in to avoid observation * Cryptic era, earliest period of the Earth ...

that induces a mutation in premature Lamin A with the deletion of a 50

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

s group near the

C-terminus The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...

. The endopeptidase

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 subs ...

cannot cleave between the missing RSY - LLG amino acid sequence (as seen in the figure) 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 In genetics, 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 a sufficiently larg ...

within

exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequen ...

11 of the LMNA gene causing the post-translational modifications to produce Progerin. Biogenesis of lamin A in normal cells and the failure to generate mature lamin A in HGPS

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

Lamin A constitutes a major structural component of the

lamina Lamina may refer to: Science and technology * Planar lamina, a two-dimensional planar closed surface with mass and density, in mathematics * Laminar flow, (or streamline flow) occurs when a fluid flows in parallel layers, with no disruption betwee ...

, a scaffold of proteins found inside the

nuclear membrane The nuclear envelope, also known as the nuclear membrane, is made up of two lipid bilayer membranes that in eukaryotic cells surround the nucleus, which encloses the genetic material. The nuclear envelope consists of two lipid bilayer membrane ...

of a

cell Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Locations * Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery ...

; progerin does not properly integrate into the lamina, which disrupts the scaffold structure and leads to significant disfigurement of the nucleus, characterized by a globular shape. Progerin activates genes that regulate

stem cell In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can differentiate into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type o ...

differentiation via the

Notch signaling pathway The Notch signaling pathway is a highly Conserved sequence, conserved cell signaling system present in most animals. Mammals possess four different Notch proteins, notch receptors, referred to as NOTCH1, NOTCH2, Notch 3, NOTCH3, and NOTCH4. The ...

. Progerin increases the frequency of unrepaired double-strand breaks in DNA following exposure to

ionizing radiation Ionizing radiation (or ionising radiation), including nuclear radiation, consists of subatomic particles or electromagnetic waves that have sufficient energy to ionize atoms or molecules by detaching electrons from them. Some particles can travel ...

. Also, overexpression of progerin is correlated with an increase in

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 ...

relative to

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 ...

among those DNA double-strand breaks that are repaired. Furthermore, the fraction of homologous recombination events occurring by

gene conversion Gene conversion is the process by which one DNA sequence replaces a homologous sequence such that the sequences become identical after the conversion event. Gene conversion can be either allelic, meaning that one allele of the same gene replaces a ...

is increased. These findings suggest that the normal untruncated

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 lamina ...

has an important role in the proper repair of DNA double-strand breaks.

Point Mutation

c.1824 C>T (GGC -> GGT, p.Gly608Gly) is the single point nucleotide polymorphism that occurs in most patients with progeria. The mutation occurs in the region G608 in exon 11 causing the sporadic mutation resulting in the amino acid

glycine Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid (carbamic acid is unstable), with the chemical formula NH2‐ CH2‐ COOH. Glycine is one of the proteinogeni ...

GGC to an alternative version of glycine GGT known as Gly608Gly. This single nucleotide C -> T polymorphism encodes for exon 11 to delete the 50 essential amino acid groups in the maturation of Lamin A. This deletion is then what causes the mutation of premature Lamin A to become the defective protein Progerin.

Premature Aging

The defective gene in HGPS Progerin has effects on accelerated aging effects due to the conformational stress Progerin has on the

cell membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment ( ...

. Matured Lamin A is a protein that maintains the cell's structural stability along with other functions. The insertion of Progerin protein rather than the normal functioning matured Lamin A results in

DNA damage DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA da ...

along the cellular membrane causing stress which activates the protein

p53 p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often s ...

resulting in premature cellular senescence causing the rapid aging effects you see in HGPS.

Lonafarnib

Researchers are exploring

lonafarnib Lonafarnib, sold under the brand name Zokinvy, is a medication used to reduce the risk of death due to Hutchinson-Gilford progeria syndrome and for the treatment of certain processing-deficient progeroid laminopathies in people one year of age a ...

farnesyltransferase inhibitor The farnesyltransferase inhibitors (FTIs) are a class of experimental cancer drugs that target protein farnesyltransferase with the downstream effect of preventing the proper functioning of the Ras (protein), which is commonly abnormally active in ...

) as a potential pharmacological therapy against the negative effects of Progerin on nuclear morphology in HGPS. lonafarnib, so far is currently the only FDA approved treatment for HGPS.

Other Information

Recently,

rapamycin Sirolimus, also known as rapamycin and sold under the brand name Rapamune among others, is a macrolide compound that is used to coat coronary stents, prevent organ transplant rejection, treat a rare lung disease called lymphangioleiomyomatosis, ...

has been shown to prevent Progerin aggregates in cells and hence delay premature aging. Progerin, which has been linked to normal

aging Ageing ( BE) or aging ( AE) is the process of becoming older. The term refers mainly to humans, many other animals, and fungi, whereas for example, bacteria, perennial plants and some simple animals are potentially biologically immortal. In ...

, is produced in healthy individuals via "sporadic use of the cryptic splice site".{{Cite journal , last1=Liu , first1=Baohua , last2=Zhou , first2=Zhongjun , date=June 2008 , title=Lamin A/C, laminopathies and premature ageing , url=https://pubmed.ncbi.nlm.nih.gov/18366013 , journal=Histology and Histopathology , volume=23 , issue=6 , pages=747–763 , doi=10.14670/HH-23.747 , issn=1699-5848 , pmid=18366013

References

Aging-related proteins Human proteins