Lemire Joan M, Patis Carrie, Gordon Leslie B, Sandy John D, Toole Bryan P, Weiss Anthony S
Department of Anatomy and Cellular Biology, Tufts University School of Medicine, Boston, MA, USA.
Mech Ageing Dev. 2006 Aug;127(8):660-9. doi: 10.1016/j.mad.2006.03.004. Epub 2006 May 2.
Hutchinson-Gilford Progeria syndrome (HGPS) is a rare genetic disorder that displays features of segmental aging. It is manifested predominantly in connective tissue, with most prominent histological changes occurring in the skin, cartilage, bone and cardiovascular tissues. Detailed quantitative real time reverse-transcription polymerase chain reaction studies confirmed the previous observation that platelet-derived growth factor A-chain transcripts are consistently elevated 11+/-2- to 13+/-2-fold in two HGPS dermal fibroblast lines compared with age-matched controls. Furthermore, we identified two additional genes with substantially altered transcript levels. Nucleotide pyrophosphatase transcription was virtually shut down with decreased expression of 13+/-3- to 59+/-3-fold in HGPS, whereas aggrecan mRNA was elevated to 24+/-5 times to 41+/-4 times that of chronologically age-matched controls. Aggrecan, normally a component of cartilage and not always detectable in normal fibroblasts cultures, was secreted by HGPS fibroblast lines and was produced as a proteoglycan. This demonstrates that elevated aggrecan expression and its secretion are aberrant features of HGPS. We conclude that HGPS cells can display massively altered transcript levels leading to the secretion of inappropriate protein species.
哈钦森-吉尔福德早衰综合征（HGPS）是一种罕见的遗传性疾病，表现出局部衰老的特征。它主要在结缔组织中表现出来，最显著的组织学变化发生在皮肤、软骨、骨骼和心血管组织中。详细的定量实时逆转录聚合酶链反应研究证实了之前的观察结果，即与年龄匹配的对照相比，两种HGPS真皮成纤维细胞系中血小板衍生生长因子A链转录本持续升高11±2至13±2倍。此外，我们还鉴定出另外两个转录水平发生显著变化的基因。在HGPS中，核苷酸焦磷酸酶转录几乎完全关闭，表达下降13±3至59±3倍，而聚集蛋白聚糖mRNA升高至按时间顺序年龄匹配对照的24±5倍至41±4倍。聚集蛋白聚糖通常是软骨的一种成分，在正常成纤维细胞培养物中并不总是可检测到，它由HGPS成纤维细胞系分泌，并作为蛋白聚糖产生。这表明聚集蛋白聚糖表达升高及其分泌是HGPS的异常特征。我们得出结论，HGPS细胞可表现出大量改变的转录水平，导致分泌不适当的蛋白质种类。
