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

Robert D. Goldman*, Dale K. Shumaker, Michael R. Erdos, Maria Eriksson, Anne E. Goldman, Leslie B. Gordon, Yosef Gruenbaum, Satya Khuon, Melissa Mendez, Renée Varga, Francis S. Collins

*Corresponding author for this work

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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.

Original languageEnglish (US)
Pages (from-to)8963-8968
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number24
DOIs
StatePublished - Jun 15 2004

ASJC Scopus subject areas

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    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. (2004). Accumulation of mutant lamin A progressive changes in nuclear architecture in Hutchinson-Gilford progeria syndrome. Proceedings of the National Academy of Sciences of the United States of America, 101(24), 8963-8968. https://doi.org/10.1073/pnas.0402943101