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Human Molecular Genetics Advance Access published online on February 15, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl026
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© The Author 2006. Published by Oxford University Press. All rights reserved
Received December 22, 2005
Revised January 27, 2006
Accepted February 9, 2006

Article

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

Erwan Delbarre 1, Marc Tramier 1, Maïté Coppey-Moisan 1, Claire Gaillard 1, Jean-Claude Courvalin 1, and Brigitte Buendia 1 *

1 Département de Biologie Cellulaire, Institut Jacques Monod, CNRS, Université Paris 6 & 7, 2 Place Jussieu, 75251 Paris Cedex 05, France

* To whom correspondence should be addressed.
Brigitte Buendia, E-mail: courvalin_submit{at}ijm.jussieu.fr


  Abstract

Hutchinson-Gilford progeria syndrome (HGPS) is a dominant autosomal premature aging syndrome caused by the expression of a truncated prelamin A designated progerin. 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 coassemble. 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 progerin expression. We studied the polymerization of EGFP- and DsRed-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 (tdFLIM) 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 progerin coassembles 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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