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Human Molecular Genetics Advance Access originally published online on February 15, 2006
Human Molecular Genetics 2006 15(7):1113-1122; doi:10.1093/hmg/ddl026
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

The truncated prelamin A in Hutchinson–Gilford progeria syndrome alters segregation of A-type and B-type lamin homopolymers

Erwan Delbarre1, Marc Tramier1, Maïté Coppey-Moisan1, Claire Gaillard2, Jean-Claude Courvalin1 and Brigitte Buendia1,*

1Département de Biologie Cellulaire, Institut Jacques Monod, CNRS, Université Paris 6 and 7, 2 Place Jussieu Tour 43, 75251 Paris Cedex 05, France and 2Centre de Recherches Biomédicales des Cordeliers, 15 rue de l'École de Médecine, 75006 Paris, France

* To whom correspondence should be addressed. Tel: +33 144277765; Fax: +33 144275994; Email: courvalin_submit{at}ijm.jussieu.fr

Received December 22, 2005; Revised January 27, 2006; Accepted February 9, 2006

Hutchinson–Gilford progeria syndrome (HGPS) is a dominant autosomal premature aging syndrome caused by the expression of a truncated prelamin A designated progerin (Pgn). A-type and B-type lamins are intermediate filament proteins that polymerize to form the nuclear lamina network apposed to the inner nuclear membrane of vertebrate somatic cells. It is not known if in vivo both type of lamins assemble independently or co-assemble. The blebbing and disorganization of the nuclear envelope and adjacent heterochromatin in cells from patients with HGPS is a hallmark of the disease, and the ex vivo reversal of this phenotype is considered important for the development of therapeutic strategies. Here, we investigated the alterations in the lamina structure that may underlie the disorganization caused in nuclei by Pgn expression. We studied the polymerization of enhanced green fluorescent protein- and red fluorescent protein-tagged wild-type and mutated lamins in the nuclear envelope of living cells by measuring fluorescence resonance energy transfer (FRET) that occurs between the two fluorophores when tagged lamins interact. Using time domain fluorescence lifetime imaging microscopy that allows a quantitative analysis of FRET signals, we show that wild-type lamins A and B1 polymerize in distinct homopolymers that further interact in the lamina. In contrast, expressed Pgn co-assembles with lamin B1 and lamin A to form a mixed heteropolymer in which A-type and B-type lamin segregation is lost. We propose that such structural lamina alterations may be part of the primary mechanisms leading to HGPS, possibly by impairing functions specific for each lamin type such as nuclear membrane biogenesis, signal transduction, nuclear compartmentalization and gene regulation.


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