The DOI matches its Crossref record; 33 of the 33 references it cites were found in a registry or an index.
Inhibiting farnesylation of progerin prevents the characteristic nuclear blebbing of Hutchinson-Gilford progeria syndrome
Open accessAbstract
Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder that is characterized by dramatic premature aging and accelerated cardiovascular disease. HGPS is almost always caused by a de novo point mutation in the lamin A gene ( LMNA ) that activates a cryptic splice donor site, producing a truncated mutant protein termed “progerin.” WT prelamin A is anchored to the nuclear envelope by a farnesyl isoprenoid lipid. Cleavage of the terminal 15 aa and the farnesyl group releases mature lamin A from this tether. In contrast, this cleavage site is deleted in progerin. We hypothesized that retention of the farnesyl group causes progerin to become permanently anchored in the nuclear membrane, disrupting proper nuclear scaffolding and causing the characteristic nuclear blebbing seen in HGPS cells. Also, we hypothesized that blocking farnesylation would decrease progerin toxicity. To test this hypothesis, the terminal CSIM sequence in progerin was mutated to SSIM, a sequence that cannot be farnesylated. SSIM progerin relocalized from the nuclear periphery into nucleoplasmic aggregates and produced no nuclear blebbing. Also, blocking farnesylation of authentic progerin in transiently transfected HeLa, HEK 293, and NIH 3T3 cells with farnesyltransferase inhibitors (FTIs) restored normal nuclear architecture. Last, treatment of both early- and late-passage human HGPS fibroblasts with FTIs resulted in significant reductions in nuclear blebbing. Our results suggest that treatment with FTIs represents a potential therapy for patients with HGPS.
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Cites
Tests for Linear Trends in Proportions and Frequencies
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Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome
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Self-citationLamin a truncation in Hutchinson-Gilford progeria
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Loss of a-Type Lamin Expression Compromises Nuclear Envelope Integrity Leading to Muscular Dystrophy
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Self-citationK- and N-Ras Are Geranylgeranylated in Cells Treated with Farnesyl Protein Transferase Inhibitors
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Inhibition of purified p21ras farnesyl:protein transferase by Cys-AAX tetrapeptides
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Nuclear lamins: building blocks of nuclear architecture
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Cited by
Mutant nuclear lamin A leads to progressive alterations of epigenetic control in premature aging
Shumaker, D. K., Dechat, T., Kohlmaier, A., Adam, S. A., Bozovsky, M. R., Erdos, M. R., Eriksson, M., Goldman, A. E., Khuon, S., Collins, F. S., et al. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0602569103 · Cited by 791
Self-citationHuman iPSC-based modeling of late-onset disease via progerin-induced aging
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Human laminopathies: nuclei gone genetically awry
Capell, B. C., & Collins, F. S. (2006) · Nature Reviews Genetics · doi:10.1038/nrg1906 · Cited by 527
Self-citationChemical inhibition of NAT10 corrects defects of laminopathic cells
Larrieu, D., Britton, S., Demir, M., Rodriguez, R., & Jackson, S. P. (2014) · Science · doi:10.1126/science.1252651 · Cited by 431
Nuclear lamins and laminopathies
Worman, H. J. (2012) · The Journal of Pathology · doi:10.1002/path.2999 · Cited by 401
Metadata
- Authors
- Capell, B. C., Erdos, M. R., Madigan, J. P., Fiordalisi, J. J., Varga, R., Conneely, K. N., Gordon, L. B., Der, C. J., Cox, A. D., & Collins, F. S.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 2005-08-29
- Volume
- 102
- Issue
- 36
- Pages
- 12879-12884
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2141334538
- Cited by
- 398
- References
- 33
- FWCI
- 8.30
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Capell, B. C., Erdos, M. R., Madigan, J. P., Fiordalisi, J. J., Varga, R., Conneely, K. N., Gordon, L. B., Der, C. J., Cox, A. D., & Collins, F. S. (2005). Inhibiting farnesylation of progerin prevents the characteristic nuclear blebbing of Hutchinson-Gilford progeria syndrome. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.0506001102
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