Accumulation of mutant lamin A causes progressive changes in nuclear architecture in Hutchinson–Gilford progeria syndrome
Open accessAbstract
Hutchinson–Gilford progeria syndrome (HGPS) is a premature aging disorder, commonly caused by a point mutation in the lamin A gene that results in a protein lacking 50 aa near the C terminus, denoted LAΔ50. Here we show by light and electron microscopy that HGPS is associated with significant changes in nuclear shape, including lobulation of the nuclear envelope, thickening of the nuclear lamina, loss of peripheral heterochromatin, and clustering of nuclear pores. These structural defects worsen as HGPS cells age in culture, and their severity correlates with an apparent increase in LAΔ50. Introduction of LAΔ50 into normal cells by transfection or protein injection induces the same changes. We hypothesize that these alterations in nuclear structure are due to a concentration-dependent dominant-negative effect of LAΔ50, leading to the disruption of lamin-related functions ranging from the maintenance of nuclear shape to regulation of gene expression and DNA replication.
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HGPS patients suffer laminopathy due to a sporadic deficiency in proteolytic processing of prelamin A into mature lamin A.
“Hutchison-Gilford progeria syndrome (HGPS) patients suffer from a variety of laminopathy ailments due to a sporadic deficiency in the proteolytic processing of the precursor form of lamin A into the mature protein.”
From Xeroderma Pigmentosa Group A (XPA), Nucleotide Excision Repair and Regulation by ATR in Response to Ultraviolet Irradiation (2017) · cites this paper as [106]
Progerin is a truncated lamin A with a hydrophobic farnesylated C-terminal.
“The aberrantly processed protein produced is called progerin, a truncated form of lamin A with a hydrophobic farnesylated C-terminal 105–112.”
From Xeroderma Pigmentosa Group A (XPA), Nucleotide Excision Repair and Regulation by ATR in Response to Ultraviolet Irradiation (2017) · cites this paper as [106]
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- Authors
- Goldman, R. D., Shumaker, D. K., Erdos, M. R., Eriksson, M., Goldman, A. E., Gordon, L. B., Gruenbaum, Y., Khuon, S., Mendez, M., Varga, R., & Collins, F. S.
- Affiliations
- Northwestern University (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2004-06-07
- Volume
- 101
- Issue
- 24
- Pages
- 8963-8968
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC428455
- OpenAlex
- W2127708563
- Cited by
- 1,103
- References
- 32
- Citations by year
- 2026: 36 · 2025: 44 · 2024: 41 · 2023: 50 · 2022: 53 · 2021: 58 · 2020: 57 · 2019: 53 · 2018: 58 · 2017: 55 · 2016: 47 · 2015: 41 · 2014: 52 · 2013: 46 · 2012: 47
- FWCI
- 18.63
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Progeria Research Foundation
- Turun Yliopisto
- National Human Genome Research Institute
- National Cancer Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Skin and Cellular Biology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Keywords
- Hutchinson-Gilford progeria syndrome, lamin A, nuclear organization, heterochromatin loss, premature aging, dominant negative effect, DNA replication
- MeSH terms
- Aged, Aged, 80 and over, Aging, Cell Cycle, Cell Nucleus, Female, Fibroblasts, Humans, Infant, Mitosis, Nuclear Envelope, Progeria, Cellular Senescence, Sequence Deletion, Cell Nucleus Structures, Lamin Type A
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