Mounkes Leslie C, Kozlov Serguei, Hernandez Lidia, Sullivan Teresa, Stewart Colin L
Cancer and Developmental Biology Laboratory, National Cancer Institute, Frederick, Maryland 21702, USA.
Nature. 2003 May 15;423(6937):298-301. doi: 10.1038/nature01631.
Numerous studies of the underlying causes of ageing have been attempted by examining diseases associated with premature ageing, such as Werner's syndrome and Hutchinson-Gilford progeria syndrome (HGPS). HGPS is a rare genetic disorder resulting in phenotypes suggestive of accelerated ageing, including shortened stature, craniofacial disproportion, very thin skin, alopecia and osteoporosis, with death in the early teens predominantly due to atherosclerosis. However, recent reports suggest that developmental abnormalities may also be important in HGPS. Here we describe the derivation of mice carrying an autosomal recessive mutation in the lamin A gene (Lmna) encoding A-type lamins, major components of the nuclear lamina. Homozygous mice display defects consistent with HGPS, including a marked reduction in growth rate and death by 4 weeks of age. Pathologies in bone, muscle and skin are also consistent with progeria. The Lmna mutation resulted in nuclear morphology defects and decreased lifespan of homozygous fibroblasts, suggesting premature cell death. Here we present a mouse model for progeria that may elucidate mechanisms of ageing and development in certain tissue types, especially those developing from the mesenchymal cell lineage.
通过研究与早衰相关的疾病，如沃纳综合征和哈钦森 - 吉尔福德早衰综合征（HGPS），人们对衰老的潜在原因进行了大量研究。HGPS是一种罕见的遗传性疾病，会导致出现加速衰老的表型，包括身材矮小、颅面比例失调、皮肤极薄、脱发和骨质疏松，青少年早期主要因动脉粥样硬化而死亡。然而，最近的报告表明，发育异常在HGPS中可能也很重要。在此，我们描述了携带编码A型核纤层蛋白（核纤层的主要成分）的核纤层蛋白A基因（Lmna）常染色体隐性突变的小鼠的培育过程。纯合子小鼠表现出与HGPS一致的缺陷，包括生长速率显著降低，4周龄时死亡。骨骼、肌肉和皮肤的病变也与早衰一致。Lmna突变导致核形态缺陷和纯合成纤维细胞寿命缩短，提示细胞过早死亡。在此，我们提出了一种早衰小鼠模型，该模型可能阐明某些组织类型，特别是那些从中胚层细胞谱系发育而来的组织类型中的衰老和发育机制。
