Hutchinson-Gilford progeria mutant lamin A primarily targets human vascular cells as detected by an anti-lamin A G608G antibody

被引:163
作者
McClintock, D
Gordon, LB
Djabali, K [1 ]
机构
[1] Columbia Univ, Coll Phys & Surg, Dept Dermatol, New York, NY 10032 USA
[2] Brown Univ, Sch Med, Dept Pediat, Providence, RI 02912 USA
关键词
aging; atherosclerosis;
D O I
10.1073/pnas.0511133103
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
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页码:2154 / 2159
页数:6
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