{{short description|Mutant lamin A protein}} {{copy edit|date=April 2026}} '''Progerin''' (UniProt# P02545-6) is a truncated version of the lamin A protein involved in the pathology of Hutchinson–Gilford progeria syndrome (HGPS). Progerin is most often generated by a sporadic single point nucleotide polymorphism {{grey|c.1824 C>T (GGC -> GGT, p.Gly608Gly)}}{{huh|date=April 2026}} in the gene that codes for matured Lamin A.<ref>{{Cite journal |last1=McClintock |first1=Dayle |last2=Gordon |first2=Leslie B. |last3=Djabali |first3=Karima |date=2006-02-14 |title=Hutchinson–Gilford progeria mutant lamin A primarily targets human vascular cells as detected by an anti-Lamin A G608G antibody |journal=Proceedings of the National Academy of Sciences |language=en |volume=103 |issue=7 |pages=2154–2159 |doi=10.1073/pnas.0511133103 |issn=0027-8424 |pmc=1413759 |pmid=16461887|bibcode=2006PNAS..103.2154M |doi-access=free }}</ref> This mutation activates a cryptic splice site that induces a larger mutation in the processed prelamin A messenger RNA, causing the deletion of a 50 amino-acid group near the C-terminus of the prelamin A protein.<ref>{{Cite journal |last1=Eriksson |first1=Maria |last2=Brown |first2=W. Ted |last3=Gordon |first3=Leslie B. |last4=Glynn |first4=Michael W. |last5=Singer |first5=Joel |last6=Scott |first6=Laura |last7=Erdos |first7=Michael R. |last8=Robbins |first8=Christiane M. |last9=Moses |first9=Tracy Y. |last10=Berglund |first10=Peter |last11=Dutra |first11=Amalia |date=May 2003 |title=Recurrent de novo point mutations in lamin A cause Hutchinson–Gilford progeria syndrome |journal=Nature |language=en |volume=423 |issue=6937 |pages=293–298 |doi=10.1038/nature01629 |pmid=12714972 |pmc=10540076 |bibcode=2003Natur.423..293E |hdl=2027.42/62684 |s2cid=4420150 |issn=0028-0836}}</ref> The endopeptidase ZMPSTE24 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 within exon 11 of the ''LMNA'' gene causing the post-translational modifications to produce progerin.<ref>{{Citation |last1=Gordon |first1=Leslie B. |title=Hutchinson-Gilford Progeria Syndrome |date=1993 |url=https://www.ncbi.nlm.nih.gov/books/NBK1121/ |work=GeneReviews® |editor-last=Adam |editor-first=Margaret P. |place=Seattle (WA) |publisher=University of Washington, Seattle |pmid=20301300 |access-date=2022-04-26 |last2=Brown |first2=W. Ted |last3=Collins |first3=Francis S. |editor2-last=Ardinger |editor2-first=Holly H. |editor3-last=Pagon |editor3-first=Roberta A. |editor4-last=Wallace |editor4-first=Stephanie E.}}</ref> thumb|400px|Normal (left) prelamin A processing and the defective gene Progerin (right) without the 50 AA sequence processing.Lamin A constitutes a major structural component of the lamina, a scaffold of proteins found inside the nuclear membrane of a cell; 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.<ref>{{Cite web |title=Anti-cancer Drugs May Hold Promise For Premature Aging Disorder |url=https://www.sciencedaily.com/releases/2005/08/050830065132.htm |access-date=2022-04-26 |website=ScienceDaily |language=en}}</ref> Progerin activates genes that regulate stem cell differentiation via the Notch signaling pathway.<ref name=":0">{{Cite journal |last1=Scaffidi |first1=Paola |last2=Misteli |first2=Tom |date=April 2008 |title=Lamin A-dependent misregulation of adult stem cells associated with accelerated ageing |journal=Nature Cell Biology |volume=10 |issue=4 |pages=452–459 |doi=10.1038/ncb1708 |issn=1476-4679 |pmc=2396576 |pmid=18311132}}</ref> Progerin increases the frequency of unrepaired double-strand breaks in DNA following exposure to ionizing radiation.<ref name=":1">{{Cite journal |last1=Noda |first1=Asao |last2=Mishima |first2=Shuji |last3=Hirai |first3=Yuko |last4=Hamasaki |first4=Kanya |last5=Landes |first5=Reid D. |last6=Mitani |first6=Hiroshi |last7=Haga |first7=Kei |last8=Kiyono |first8=Tohru |last9=Nakamura |first9=Nori |last10=Kodama |first10=Yoshiaki |date=December 2015 |title=Progerin, the protein responsible for the Hutchinson-Gilford progeria syndrome, increases the unrepaired DNA damages following exposure to ionizing radiation |journal=Genes and Environment |language=en |volume=37 |issue=1 |pages=13 |doi=10.1186/s41021-015-0018-4 |issn=1880-7062 |pmc=4917958 |pmid=27350809 |doi-access=free }}</ref> Also, overexpression of progerin is correlated with an increase in non-homologous end joining relative to homologous recombination among those DNA double-strand breaks that are repaired.<ref>{{Cite journal |last1=Komari |first1=Celina J. |last2=Guttman |first2=Anne O. |last3=Carr |first3=Shelby R. |last4=Trachtenberg |first4=Taylor L. |last5=Orloff |first5=Elise A. |last6=Haas |first6=Ashley V. |last7=Patrick |first7=Andrew R. |last8=Chowdhary |first8=Sona |last9=Waldman |first9=Barbara C. |last10=Waldman |first10=Alan S. |date=December 2020 |title=Alteration of genetic recombination and double-strand break repair in human cells by progerin expression |journal=DNA Repair |language=en |volume=96 |article-number=102975 |doi=10.1016/j.dnarep.2020.102975 |pmc=7669652 |pmid=33010688}}</ref> Furthermore, the fraction of homologous recombination events occurring by gene conversion is increased. These findings suggest that the normal untruncated nuclear lamina has an important role in the proper repair of DNA double-strand breaks.<ref name=":1" />
== 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 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.<ref>{{Cite journal |last1=Piekarowicz |first1=Katarzyna |last2=Machowska |first2=Magdalena |last3=Dzianisava |first3=Volha |last4=Rzepecki |first4=Ryszard |date=February 2019 |title=Hutchinson-Gilford Progeria Syndrome—Current Status and Prospects for Gene Therapy Treatment |journal=Cells |language=en |volume=8 |issue=2 |pages=88 |doi=10.3390/cells8020088 |issn=2073-4409 |pmc=6406247 |pmid=30691039|doi-access=free }}</ref> 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. Matured Lamin A is a protein that maintains the cell's structural stability along with other functions.<ref>{{Cite journal |last1=Dubik |first1=Niina |last2=Mai |first2=Sabine |date=2020-12-09 |title=Lamin A/C: Function in Normal and Tumor Cells |journal=Cancers |language=en |volume=12 |issue=12 |pages=3688 |doi=10.3390/cancers12123688 |issn=2072-6694 |pmc=7764147 |pmid=33316938|doi-access=free }}</ref> The insertion of Progerin protein rather than the normal functioning matured Lamin A results in DNA damage along the cellular membrane. This causes stress which activates the protein p53, resulting in premature cellular senescence, causing the rapid aging effects observed in HGPS.
Rapamycin has been shown to prevent Progerin aggregates in cells and hence delay premature aging.<ref>{{Cite journal |last=Selvarani |first=Ramasamy |last2=Mohammed |first2=Sabira |last3=Richardson |first3=Arlan |date=June 2021 |title=Effect of rapamycin on aging and age-related diseases-past and future |url=https://pmc.ncbi.nlm.nih.gov/articles/PMC8190242/ |journal=GeroScience |volume=43 |issue=3 |pages=1135–1158 |doi=10.1007/s11357-020-00274-1 |issn=2509-2723 |pmc=8190242 |pmid=33037985}}</ref>
== Lonafarnib == Researchers are exploring lonafarnib (a farnesyltransferase inhibitor) as a potential pharmacological therapy against the negative effects of Progerin on nuclear morphology in HGPS. Lonafarnib is currently the only FDA approved treatment for HGPS.<ref>{{Cite journal |last=Dhillon |first=Sohita |date=February 2021 |title=Lonafarnib: First Approval |journal=Drugs |language=en |volume=81 |issue=2 |pages=283–289 |doi=10.1007/s40265-020-01464-z |issn=0012-6667 |pmc=7985116 |pmid=33590450}}</ref>
=== Other information === Progerin, which has been linked to normal ageing, is produced in healthy individuals via "sporadic use of the cryptic splice site".<ref name=":0" /><ref>{{Cite journal |last1=Liu |first1=Baohua |last2=Zhou |first2=Zhongjun |date=June 2008 |title=Lamin A/C, laminopathies and premature ageing |journal=Histology and Histopathology |volume=23 |issue=6 |pages=747–763 |doi=10.14670/HH-23.747 |issn=1699-5848 |pmid=18366013}}</ref>
==References== <references />
Category:Aging-related proteins Category:Human proteins