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

*Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892; and
^†Department of Dermatology, College of Physicians and Surgeons, Columbia University, New York, NY 10032

Contributed by Francis S. Collins, December 29, 2006 (received for review December 20, 2006)

Abstract

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.

Footnotes

^‡To whom correspondence should be addressed. E-mail: fc23a{at}nih.gov
Author contributions: K.C. and F.S.C. designed research; K.C. and B.C.C. performed research; K.C. and K.D. contributed new reagents/analytic tools; K.C., M.R.E., and F.S.C. analyzed data; and K.C. and F.S.C. wrote the paper.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/cgi/content/full/0611640104/DC1.
Abbreviations:

HGPS,

Hutchinson–Gilford progeria syndrome;

LA,

lamin A;

FTI,

farnesyl transferase inhibitor;

NE,

nuclear envelope;

FLIP,

fluorescence loss in photobleaching;

FRAP,

fluorescence recovery after photobleaching.
Freely available online through the PNAS open access option.