ArticleHuman molecular genetics2011
Absence of progeria-like disease phenotypes in knock-in mice expressing a non-farnesylated version of progerin.
Article in Human molecular genetics, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed, 71 citations in OpenAlex.
- Mutation-agnostic base editing of the progerin farnesylation site rescues Hutchinson-Gilford progeria syndrome phenotypes in neuromuscular organoids.Nature communications · 2026Article
- Progerin-induced nuclear envelope remodeling is shaped by cell division and NUP153.Journal of cell science · 2026Article
- The accumulation of progerin underlies the loss of aortic smooth muscle cells in Hutchinson-Gilford progeria syndrome.Cell death & disease · 2025Article
- Progerin forms an abnormal meshwork and has a dominant-negative effect on the nuclear lamina.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Genetic and pharmacological modulation of lamin A farnesylation determines its function and turnover.Aging cell · 2024Article
- The farnesyl transferase inhibitor (FTI) lonafarnib improves nuclear morphology in ZMPSTE24-deficient fibroblasts from patients with the progeroid disorder MAD-B.Nucleus (Austin, Tex.) · 2023Article
- Epigenetics inCells · 2023Review
- Pharmacotherapy to gene editing: potential therapeutic approaches for Hutchinson-Gilford progeria syndrome.GeroScience · 2020Review
- Hutchinson-Gilford Progeria Syndrome-Current Status and Prospects for Gene Therapy Treatment.Cells · 2019Review
- Are There Common Mechanisms Between the Hutchinson-Gilford Progeria Syndrome and Natural Aging?Frontiers in genetics · 2019Review
- Genomic instability and DNA replication defects in progeroid syndromes.Nucleus (Austin, Tex.) · 2018Review
- Expression of progerin does not result in an increased mutation rate.Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology · 2017Article
- Identification of novel RNA isoforms of LMNA.Nucleus (Austin, Tex.) · 2017Article
- LMNA missense mutations causing familial partial lipodystrophy do not lead to an accumulation of prelamin A.Nucleus (Austin, Tex.) · 2016Article
- Molecular insights into the premature aging disease progeria.Histochemistry and cell biology · 2016Review
- A high-content imaging-based screening pipeline for the systematic identification of anti-progeroid compounds.Methods (San Diego, Calif.) · 2016Article
- Protein prenylation: unique fats make their mark on biology.Nature reviews. Molecular cell biology · 2016Review
- Mutant lamin A links prophase to a p53 independent senescence program.Cell cycle (Georgetown, Tex.) · 2015Article
- iTRAQ-based analysis of progerin expression reveals mitochondrial dysfunction, reactive oxygen species accumulation and altered proteostasis.Stem cell research & therapy · 2015Article
- Preventing farnesylation of the dynein adaptor Spindly contributes to the mitotic defects caused by farnesyltransferase inhibitors.Molecular biology of the cell · 2015Article
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
Hutchinson-Gilford progeria syndrome (HGPS) is caused by a mutant prelamin A, progerin, that terminates with a farnesylcysteine. HGPS knock-in mice (Lmna(HG/+)) develop severe progeria-like disease phenotypes. These phenotypes can be ameliorated with a protein farnesyltransferase inhibitor (FTI), suggesting that progerin's farnesyl lipid is important for disease pathogenesis and raising the possibility that FTIs could be useful for treating humans with HGPS. Subsequent studies showed that mice expressing non-farnesylated progerin (Lmna(nHG/+) mice, in which progerin's carboxyl-terminal -CSIM motif was changed to -SSIM) also develop severe progeria, raising doubts about whether any treatment targeting protein prenylation would be particularly effective. We suspected that those doubts might be premature and hypothesized that the persistent disease in Lmna(nHG/+) mice could be an unanticipated consequence of the cysteine-to-serine substitution that was used to eliminate farnesylation. To test this hypothesis, we generated a second knock-in allele yielding non-farnesylated progerin (Lmna(csmHG)) in which the carboxyl-terminal -CSIM motif was changed to -CSM. We then compared disease phenotypes in mice harboring the Lmna(nHG) or Lmna(csmHG) allele. As expected, Lmna(nHG/+) and Lmna(nHG/nHG) mice developed severe progeria-like disease phenotypes, including osteolytic lesions and rib fractures, osteoporosis, slow growth and reduced survival. In contrast, Lmna(csmHG/+) and Lmna(csmHG/csmHG) mice exhibited no bone disease and displayed entirely normal body weights and survival. The frequencies of misshapen cell nuclei were lower in Lmna(csmHG/+) and Lmna(csmHG/csmHG) fibroblasts. These studies show that the ability of non-farnesylated progerin to elicit disease depends on the carboxyl-terminal mutation used to eliminate protein prenylation.
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