Cited by 1,103Nuclear Structure and FunctionSkin and Cellular Biology ResearchDNA Repair Mechanisms

Accumulation of mutant lamin A causes progressive changes in nuclear architecture in Hutchinson–Gilford progeria syndrome

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Goldman, Robert D., Shumaker, Dale K., Erdos, Michael R., Eriksson, Maria, Goldman, Anne E., Gordon, Leslie B., Gruenbaum, Yosef, Khuon, Satya +3 more·2004·Proceedings of the National Academy of Sciences

Abstract

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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Crossref · 10.1073/pnas.0402943101

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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)
Venue
Proceedings of the National Academy of Sciences
Published
2004-06-07
Volume
101
Issue
24
Pages
8963-8968
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
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
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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