Delbarre, E. et al. The truncated prelamin A in Hutchinson-Gilford progeria syndrome alters segregation of A-type and B-type lamin homopolymers. Hum. Mol. Genet. 15, 1113-1122

Département de Biologie Cellulaire, Institut Jacques Monod, CNRS, Université Paris 6 and 7, 2 Place Jussieu Tour 43, 75251 Paris Cedex 05, France.
Human Molecular Genetics (Impact Factor: 6.39). 05/2006; 15(7):1113-22. DOI: 10.1093/hmg/ddl026
Source: PubMed


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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Available from: Marc Tramier, Feb 12, 2014
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    • "It has been observed in vivo that A-and B-type lamins preferentially form homopolymers and that heterotypic interaction of lamins occurs between juxtaposed A-and B-type lamin homopolymers [39]. Furthermore , it was reported in amphibian oocytes that different lamin proteins form distinctive individual filaments with characteristic organization . "
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    • "In addition, the LA/C meshwork in the NE of LMNB D/D MEFs exhibits a dramatic increase in mesh size (Vergnes et al., 2004). Additional evidence for interaction between these two lamin meshworks comes from studies using fluorescence resonance energy transfer (FRET) in combination with time domain fluorescence lifetime imaging and high resolution confocal immunofluorescence (Delbarre et al., 2006; Moir et al., 2000; Shimi et al., 2008). A small but significant fraction of both A-and B-type lamins are also present throughout the nuclear interior during interphase. "

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    • "However, B type lamins undergo partial proteolysis by the enzyme Rce1 and remain permanently farnesylated. Farnesylation of B type lamins has been implicated in their anchorage to the nuclear membrane, but might also mediate protein–protein interactions [Maske et al., 2003; Delbarre et al., 2006]. EMERIN Emerin is the first nuclear envelope protein associated with laminopathies [Bione et al., 1994]. "
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