A lamin A protein isoform overexpressed in Hutchinson–Gilford progeria syndrome interferes with mitosis in progeria and normal cells

K Cao, BC Capell, MR Erdos… - Proceedings of the …, 2007 - National Acad Sciences
Proceedings of the National Academy of Sciences, 2007National Acad Sciences
Hutchinson–Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by
dramatic premature aging. Classic HGPS is caused by a de novo point mutation in exon 11
(residue 1824, C→ T) of the LMNA gene, activating a cryptic splice donor and resulting in a
mutant lamin A (LA) protein termed “progerin/LAΔ50” that lacks the normal cleavage site to
remove a C-terminal farnesyl group. During interphase, irreversibly farnesylated
progerin/LAΔ50 anchors to the nuclear membrane and causes characteristic nuclear …
Hutchinson–Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by dramatic premature aging. Classic HGPS is caused by a de novo point mutation in exon 11 (residue 1824, C → T) of the LMNA gene, activating a cryptic splice donor and resulting in a mutant lamin A (LA) protein termed “progerin/LAΔ50” that lacks the normal cleavage site to remove a C-terminal farnesyl group. During interphase, irreversibly farnesylated progerin/LAΔ50 anchors to the nuclear membrane and causes characteristic nuclear blebbing. Progerin/LAΔ50's localization and behavior during mitosis, however, are completely unknown. Here, we report that progerin/LAΔ50 mislocalizes into insoluble cytoplasmic aggregates and membranes during mitosis and causes abnormal chromosome segregation and binucleation. These phenotypes are largely rescued with either farnesyltransferase inhibitors or a farnesylation-incompetent mutant progerin/LAΔ50. Furthermore, we demonstrate that small amounts of progerin/LAΔ50 exist in normal fibroblasts, and a significant percentage of these progerin/LAΔ50-expressing normal cells are binucleated, implicating progerin/LAΔ50 as causing similar mitotic defects in the normal aging process. Our findings present evidence of mitotic abnormality in HGPS and may shed light on the general phenomenon of aging.
National Acad Sciences