Hutchinson-Gilford progeria mutant lamin A primarily targets human vascular cells as detected by an anti-Lamin A G608G antibody.
Hutchinson-Gilford progeria syndrome (HGPS; Online Mendelian Inheritance in Man accession no. 176670) is a rare disorder that is characterized by segmental premature aging and death between 7 and 20 years of age from severe premature atherosclerosis. Mutations in the LMNA gene are responsible for this syndrome. Approximately 80% of HGPS cases are caused by a G608 (GGC-->GGT) mutation within exon 11 of LMNA, which elicits a deletion of 50 aa near the C terminus of prelamin A. In this article, we present evidence that the mutant lamin A (progerin) accumulates in the nucleus in a cellular age-dependent manner. In human HGPS fibroblast cultures, we observed, concomitantly to nuclear progerin accumulation, severe nuclear envelope deformations and invaginations preventable by farnesyltransferase inhibition. Nuclear alterations affect cell-cycle progression and cell migration and elicit premature senescence. Strikingly, skin biopsy sections from a subject with HGPS showed that the truncated lamin A accumulates primarily in the nuclei of vascular cells. This finding suggests that accumulation of progerin is directly involved in vascular disease in progeria.
McClintock
Dayle
D
Department of Dermatology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Gordon
Leslie B
LB
Djabali
Karima
K
D000367:Age Factors; D019588:Aging, Premature / Q000235:genetics; D000906:Antibodies; D050197:Atherosclerosis / Q000235:genetics; D002465:Cell Movement; D002467:Cell Nucleus / Q000737:chemistry* / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000737:chemistry / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors; D005347:Fibroblasts / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D034904:Lamin Type A / Q000032:analysis* / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D011371:Progeria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012867:Skin / Q000473:pathology
D000906:Antibodies; D004791:Enzyme Inhibitors; D034904:Lamin Type A; D051231:Farnesyltranstransferase