Hutchinson-Gilford progeria mutant lamin A primarily targets human vascular cells as detected by an anti-lamin A G608G antibody
Hutchinson-Gilford progeria mutant lamin A primarily targets human vascular cells as detected by an anti-lamin A G608G antibody
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DOI：
10.1073/pnas.0511133103
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发表时间：
2006-02-14
影响因子：
11.1
通讯作者：
Djabali, K
中科院分区：
文献类型：
--
作者：
McClintock, D;Gordon, LB;Djabali, K
哈钦森-吉尔福德早衰综合征（HGPS）；在线孟德尔遗传（176670）是一种罕见的疾病，其特征是在7至20岁之间因严重的过早动脉粥样硬化而过早衰老和死亡。LMNA基因的突变是导致这种综合征的原因。大约80%的HGPS病例是由LMNA外显子11内的G608 （GGC -> GGT）突变引起的，该突变导致前纤层蛋白a C端附近缺失50 aa。在本文中，我们提出证据表明突变的纤层蛋白a （progerin）以细胞年龄依赖性的方式在细胞核中积累。在人HGPS成纤维细胞培养中，我们观察到，伴随核早衰蛋白积累，严重的核膜变形和内陷可以通过法尼基转移酶抑制来预防。细胞核改变影响细胞周期进程和细胞迁移，导致过早衰老。引人注目的是，来自HGPS患者的皮肤活检切片显示，截短的层粘胶蛋白a主要积聚在血管细胞的细胞核中。这一发现表明，早衰症血管疾病与早衰蛋白的积累有直接关系。
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.