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

Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by dramatic premature aging. Classic HGIPS 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/LA Delta 50" that lacks the normal cleavage site to remove a C-terminal farnesyl group. During interphase, irreversibly farnesylated progerin/LA Delta 50 anchors to the nuclear membrane and causes characteristic nuclear blebbing. Progerin/LA Delta 50's localization and behavior during mitosis, however, are completely unknown. Here, we report that progerin/LA Delta 50 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/LA Delta 50. Furthermore, we demonstrate that small amounts of progerin/LAA50 exist in normal fibroblasts, and a significant percentage of these progerin/LA Delta 50-expressing normal cells are binucleated, implicating progerin/LAA50 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.