Hutchinson-Gilford Progeria Mutant Lamin A Primarily Targets Human Vascular Cells as Detected by an Anti-Lamin A G608G Antibody

• Published in: Proceedings of the National Academy of Sciences - PNAS 2006-02, Vol.103 (7), p.2154-2159
• Main Authors: McClintock, Dayle, Gordon, Leslie B., Djabali, Karima
• Format: Article
• Language: English
• Subjects: Age Factors; Aging, Premature - genetics; Antibodies; Atherosclerosis - genetics; Biological Sciences; Cell growth; Cell Movement; Cell nucleus; Cell Nucleus - chemistry; Cell Nucleus - metabolism; Cell Proliferation; Cells; Cells, Cultured; Cellular immunity; Cellular senescence; Cultured cells; Endothelial cells; Endothelial Cells - chemistry; Endothelial Cells - metabolism; Enzyme Inhibitors - pharmacology; Farnesyltranstransferase - antagonists & inhibitors; Fibroblasts; Fibroblasts - chemistry; Fibroblasts - metabolism; Genetic disorders; Humans; Lamin Type A - analysis; Lamin Type A - genetics; Lamin Type A - metabolism; Lamins; Mutation; Nuclear lamina; Progeria - genetics; Progeria - metabolism; Progeria - pathology; Proteins; Skin; Skin - pathology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0511133103

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.