title: A lamin A protein isoform overexpressed in Hutchinson-Gilford progeria syndrome interferes with mitosis in progeria and normal cells.
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/LADelta50" that lacks the normal cleavage site to remove a C-terminal farnesyl group. During interphase, irreversibly farnesylated progerin/LADelta50 anchors to the nuclear membrane and causes characteristic nuclear blebbing. Progerin/LADelta50's localization and behavior during mitosis, however, are completely unknown. Here, we report that progerin/LADelta50 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/LADelta50. Furthermore, we demonstrate that small amounts of progerin/LADelta50 exist in normal fibroblasts, and a significant percentage of these progerin/LADelta50-expressing normal cells are binucleated, implicating progerin/LADelta50 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.
authors.affiliation: Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Kan
authors.initials: K
authors.lastname: Cao
authors.forename: Brian C
authors.initials: BC
authors.lastname: Capell
authors.forename: Michael R
authors.initials: MR
authors.lastname: Erdos
authors.forename: Karima
authors.initials: K
authors.lastname: Djabali
authors.forename: Francis S
authors.initials: FS
authors.lastname: Collins
mesh_terms: D005347:Fibroblasts / Q000166:cytology*; D015870:Gene Expression; D006367:HeLa Cells; D006801:Humans; D034904:Lamin Type A / Q000235:genetics / Q000378:metabolism*; D008938:Mitosis; D050505:Mutant Proteins / Q000378:metabolism; D038761:Photobleaching; D011371:Progeria / Q000473:pathology*; D020033:Protein Isoforms / Q000378:metabolism; D017368:Protein Prenylation; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014162:Transfection
chemical_list: D034904:Lamin Type A; D050505:Mutant Proteins; D020033:Protein Isoforms; D011993:Recombinant Fusion Proteins