Hutchinson-Gilford早老症的研究进展

Hutchinson-Gilford早老症（HGPS）为一种极为罕见的遗传性疾病，发生率1／8000000，特征性表现为患儿以极快速度衰老，多数死于冠脉病变引起的心肌梗死或广泛动脉粥样硬化导致的卒中，平均寿命13岁。绝大多数HGPS病例病因为LMNA基因第11个外显子发生点突变（G608G），生成的突变laminA由显性负效应造成细胞核结构和功能受损。目前该病已有几种动物模型，实验性治疗可以在体外将出泡的细胞核恢复正常。HGPS是研究衰老和心血管疾病机制的一个极好的模型。     

早老蛋白功能研究进展

分子遗传学研究表明早老蛋白基因 (PS)突变是家族性阿尔茨海默疾病家系中最常见的遗传性基因突变。因此 PS功能的研究成为近年来阿尔茨海默疾病研究领域的热点。本文综述了 PS参与调节 Notch信号通路和Wnt信号通路信号传导的研究进展 ,以及 PS与神经细胞程序性死亡的关系 ,详细讨论了 PS即 γ分泌酶这一假说 ,并概述了 PS的其它相互作用蛋白及其相互作用的生物学意义     

儿童型早老症的特征与病因研究

儿童型早老症（Hutchinson-Gilfordprogeria syndrome下称HGPS）Hutchi-nson 1886年首次在医学文献报道,1985年发表第2例简要报告。Gilford1904年发表HGPS尸体剖检所见,并作进一步描述。嗣后国外文献时有报道。国内HGPS最早记载为《实用儿科学》1973年版,中华儿科杂志6例综     

自然流产中的早孕期蜕膜细胞Bcl-2 /Bax 比例异常

探讨早孕期蜕膜细胞细胞凋亡异常与妊娠失败的关系。应用TUNEL法测定凋亡的发生及凋亡细胞的定位，免疫组化法检测Bcl-2、Bax蛋白的表达和相互关系。结果发现：（1）正常早孕40d蜕膜组织细胞大量凋亡，Bcl-2蛋白表达量较低，Bax蛋白有较强表达。（2）正常早孕50d，凋亡细胞明显减少，Bcl-2的表达显著增强，Bax蛋白表达减弱。（3）早孕50d自然流产组，蜕膜组织大量凋亡，与同时期正常蜕膜组织相比，P＜0．01。Bcl-2蛋白表达明显降低，Bax蛋白表达明显增强，Bcl-2/Bax比例降低。早孕期蜕膜组织凋亡异常可能是自然流产的机制之一，Bcl-2/Bax途径可能是诱导早孕期蜕膜细胞凋亡的重要因素。     

Alzheimer病患者和大鼠脑内早老蛋白-1的分布

用免疫组化方法和原位杂交观察散发性阿尔茨海默病 (Sporadic Alzheimer' s disease)病人和老年对照 ,以及成年大鼠脑组织内的早老蛋白 -1(Presenilin-1,PS1)分布。结果观察到 PS1在脑内广泛分布 ,其中小脑的 Purkinje细胞、皮层的第 、 层细胞、内嗅皮层的第 层、海马的锥体细胞层和颗粒细胞层、黑质等结构 PS1表达较高。在大鼠和正常对照人脑内大多数 PS1阳性神经元染色呈点状分布于胞浆内 ;而阿尔茨海默病人脑内有许多 PS1阳性神经元为均质染色并且其中有些呈神经原纤维缠结状 ,其次有大量各型 PS1阳性老年斑 ,和少量 PS1阳性胶质细胞。结果提示 PS1可能参与散发性阿尔茨海默病脑病理改变     

早孕期超声筛查异常行绒毛核型分析的意义

目的探讨早孕期超声筛查异常行绒毛核型分析的意义。方法对65例早孕期超声筛查发现异常的孕妇行绒毛核型分析。结果在65例早孕期超声筛查异常孕妇的胎儿绒毛核型中,检出异常核型28例,异常率为43.08%,主要为18-三体、21-三体和45,X。在异常的超声指征中,全身皮下水肿7例,5例核型异常;全身皮下水肿合并其他异常9例,8例核型异常;胚胎停育11例,6例核型异常;鼻骨异常合并其他异常3例,2例核型异常;NT增厚18例,4例核型异常;NT增厚合并其他异常6例,4例核型异常;多发畸形8例,3例核型异常;淋巴水囊瘤1例有核型异常。结论早孕期超声筛查异常孕妇的胎儿染色体异常率高,对其行绒毛核型分析是必要的。     

Werner综合征:结缔组织代谢、培养细胞的生长控制以及染色体畸变的最新研究

Werner综合征是一种罕见的、常染色体隐性疾病,青年人的临床症状类似于老年人。它有时被称为“成年早老症”,但Werner 综合征与正常衰老过程有明显区别。近来有证据表明,Werner 综合征被认为是类似于着色性干皮病、毛细管扩张性共济失调、Fanconi 贫血和Bloom 综合征的染色体不稳定综合征。由于本病以常染色体隐性方式遗传,所以Werner 综合征可能是由单基因缺陷或小的多基因缺失引起的。因此,它提供了研究引起衰老部分表型摸拟的各种生物学和生化学结果的机会。了解Werner综合征的基本分子缺陷,可以深入了解衰老     

端粒酶防止Werner综合征纤维母细胞衰老

遗传性家族性萎缩性皮肤病 ( Werner综合征 ,WS)是一种罕见的常染色体隐性遗传病 ,其特征为衰老加速。WS纤维母细胞在体外显示衰老率加速 ,与早老性表型连锁。有研究认为正常人纤维母细胞的衰老是受端粒缩短所致 ,而 WS纤维母细胞的早衰曾被认为反映了 DNA损伤的积累。在此作者认为 ,WS的端粒酶有力表达参与延长细胞寿命并有可能不死。WS基因 ( WRN)编码 DNA解螺旋酶 Rec Q家族一个成员。据报道 WS细胞核型不稳定 ,并显示出特有的增变基因表型。对紫外线或 X射线缺乏敏感性 ,是 WS与典型的 DNA修复综合征的区别 ,如着色性干皮病…     

衰老和凋亡对宫颈鳞状细胞癌的致癌作用

<正>目的:许多细胞周期调控因子如p14ARF、p15INK4b和p16INK4a在G1细胞周期阻滞和癌基因诱导衰老中起重要作用;bcl-2蛋白是抗凋亡成分中关键因子之一,而p53蛋白在凋亡和衰老中都起重要作用,这些关键调控因子的基因在各种恶性肿瘤中常常突变或缺如。本文研究衰老、凋亡和增殖标志物在正常宫颈上皮、宫颈上皮内瘤变(CIN)和宫颈鳞状细胞癌(SCC)中的表达。方法:每组(正常宫颈组、CIN Ⅱ-Ⅲ组和F组)40例。样本分别来源于120个宫颈活组织检查和宫颈锥形切除术。     

Klotho基因及其与衰老相关的研究现状

在小鼠中Klotho基因的表达缺失导致出现了类似于人类衰老的综合征，本文综述了Klotho基因及蛋白的结构特点、Klotho表型异常的特性和Klotho基因的研究现状。     

Hutchinson-Gilford progeria syndrome

Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare genetic disorder that causes premature, rapid aging shortly after birth. Recently, de novo point mutations in the Lmna gene have been found in individuals with HGPS. Lmna encodes lamin A and C, the A-type lamins, which are an important structural component of the nuclear envelope. The most common HGPS mutation is located at codon 608 (G608G). This mutation creates a cryptic splice site within exon 11, which deletes a proteolytic cleavage site within the expressed mutant lamin A. Incomplete processing of prelamin A results in nuclear lamina abnormalities that can be observed in immunofluorescent studies of HGPS cells. Mouse models, such as Lmna knockout, Zmpste24 knockout, and Lmna L530P knockin will help the study of progeria. Lmna mutations have also recently been found in patients with atypical forms of progeria. The discovery of the HGPS mutations brings the total number of diseases caused by mutant Lmna to nine, underscoring the astonishing spectrum of laminopathies. Future research into HGPS could also provide important clues about the general process of aging and aging-related diseases.     

Rapamycin reverses cellular phenotypes and enhances mutant protein clearance in Hutchinson-Gilford progeria syndrome cells

Hutchinson-Gilford progeria syndrome (HGPS) is a lethal genetic disorder characterized by premature aging. HGPS is most commonly caused by a de novo single-nucleotide substitution in the lamin A/C gene (LMNA) that partially activates a cryptic splice donor site in exon 11, producing an abnormal lamin A protein termed progerin. Accumulation of progerin in dividing cells adversely affects the integrity of the nuclear scaffold and leads to nuclear blebbing in cultured cells. Progerin is also produced in normal cells, increasing in abundance as senescence approaches. Here, we report the effect of rapamycin, a macrolide antibiotic that has been implicated in slowing cellular and organismal aging, on the cellular phenotypes of HGPS fibroblasts. Treatment with rapamycin abolished nuclear blebbing, delayed the onset of cellular senescence, and enhanced the degradation of progerin in HGPS cells. Rapamycin also decreased the formation of insoluble progerin aggregates and induced clearance through autophagic mechanisms in normal fibroblasts. Our findings suggest an additional mechanism for the beneficial effects of rapamycin on longevity and encourage the hypothesis that rapamycin treatment could provide clinical benefit for children with HGPS.     

Telomere length in Hutchinson-Gilford Progeria Syndrome

Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare premature aging disorder caused by mutations in the gene LMNA, which encodes the nuclear matrix protein lamin A. Previous research has shown that the average telomere length in fibroblasts from HGPS patients is shorter than in age-matched controls. How mutations in lamin A lead to shortened telomere lengths is not known nor is the contribution of individual chromosome ends to the low average length understood. To measure the telomere length of individual chromosomes, we used Quantitative Fluorescence in situ Hybridization (Q-FISH). In agreement with previous studies, we found that the average telomere length in HPGS fibroblasts is greatly reduced; however, the telomere length at chromosome ends was variable. In contrast, the telomere length in hematopoietic cells which typically do not express lamin A, was within the normal range for three out of four HGPS patient samples. Our results suggest that mutant lamin A decreases telomere length via a direct effect and that expression of mutant LMNA is necessary for telomere loss in HGPS.     

A conserved splicing mechanism of the LMNA gene controls premature aging

Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder phenotypically characterized by many features of premature aging. Most cases of HGPS are due to a heterozygous silent mutation (c.1824C>T; p.Gly608Gly) that enhances the use of an internal 5' splice site (5'SS) in exon 11 of the LMNA pre-mRNA and leads to the production of a truncated protein (progerin) with a dominant negative effect. Here we show that HGPS mutation changes the accessibility of the 5'SS of LMNA exon 11 which is sequestered in a conserved RNA structure. Our results also reveal a regulatory role of a subset of serine-arginine (SR)-rich proteins, including serine-arginine rich splicing factor 1 (SRSF1) and SRSF6, on utilization of the 5'SS leading to lamin A or progerin production and a modulation of this regulation in the presence of the c.1824C>T mutation is shown directly on HGPS patient cells. Mutant mice carrying the equivalent mutation in the LMNA gene (c.1827C>T) also accumulate progerin and phenocopy the main cellular alterations and clinical defects of HGPS patients. RNAi-induced depletion of SRSF1 in the HGPS-like mouse embryonic fibroblasts (MEFs) allowed progerin reduction and dysmorphic nuclei phenotype correction, whereas SRSF6 depletion aggravated the HGPS-like MEF's phenotype. We demonstrate that changes in the splicing ratio between lamin A and progerin are key factors for lifespan since heterozygous mice harboring the mutation lived longer than homozygous littermates but less than the wild-type. Genetic and biochemical data together favor the view that physiological progerin production is under tight control of a conserved splicing mechanism to avoid precocious aging.     

Enhanced SRSF5 Protein Expression Reinforces Lamin A mRNA Production in HeLa Cells and Fibroblasts of Progeria Patients

The Hutchinson Gilford Progeria Syndrome (HGPS) is a rare genetic disease leading to accelerated aging. Three mutations of the LMNA gene leading to HGPS were identified. The more frequent ones, c.1824C>T and c.1822G>A, enhance the use of the intron 11 progerin 5′splice site (5′SS) instead of the LMNA 5′SS, leading to the production of the truncated dominant negative progerin. The less frequent c.1868C>G mutation creates a novel 5′SS (LAΔ35 5′SS), inducing the production of another truncated LMNA protein (LAΔ35). Our data show that the progerin 5′SS is used at low yield in the absence of HGPS mutation, whereas utilization of the LAΔ35 5′SS is dependent upon the presence of the c.1868C>G mutation. In the perspective to correct HGPS splicing defects, we investigated whether SR proteins can modify the relative yields of utilization of intron 11 5′SSs. By in cellulo and in vitro assays, we identified SRSF5 as a direct key regulator increasing the utilization of the LMNA 5′SS in the presence of the HGPS mutations. Enhanced SRSF5 expression in dermal fibroblasts of HGPS patients as well as PDGF‐BB stimulation of these cells decreased the utilization of the progerin 5′SS, and improves nuclear morphology, opening new therapeutic perspectives for premature aging.     

Pluripotent stem cells to model Hutchinson-Gilford progeria syndrome (HGPS): Current trends and future perspectives for drug discovery

Progeria, or Hutchinson–Gilford progeria syndrome (HGPS), is a rare, fatal genetic disease characterized by an appearance of accelerated aging in children. This syndrome is typically caused by mutations in codon 608 (p.G608G) of the LMNA, leading to the production of a mutated form of lamin A precursor called progerin. In HGPS, progerin accumulates in cells causing progressive molecular defects, including nuclear shape abnormalities, chromatin disorganization, damage to DNA and delays in cell proliferation. Here we report how, over the past five years, pluripotent stem cells have provided new insights into the study of HGPS and opened new original therapeutic perspectives to treat the disease.     

Effect of progerin on the accumulation of oxidized proteins in fibroblasts from Hutchinson Gilford progeria patients

The mutation responsible for Hutchinson Gilford Progeria Syndrome (HGPS) causes abnormal nuclear morphology. Previous studies show that free radicals and reactive oxygen species play major roles in the etiology and/or progression of neurodegenerative diseases and aging. This study compares oxidative stress responses between progeric and normal fibroblasts. Our data revealed higher ROS levels in HGPS cells compared to age-matched controls. In response to oxidative challenge, progeric cells showed increased mRNA levels for mitochondrial superoxide dismutase (SOD) and SOD protein content. However, this did not prevent a drop in the ATP content of progeria fibroblasts. Previous studies have shown that declines in human fibroblast ATP levels interfere with programmed cell death and promote necrotic inflammation. Notably, in our investigations the ATP content of progeria fibroblasts was only ∼50% of that found in healthy controls. Furthermore, HGPS fibroblast analysis revealed a decrease in total caspase-like proteasome activity and in the levels of two active proteolytic complex subunits (β₅ and β₇). A number of studies indicate that the molecular mechanisms causing accelerated aging in progeric patients also occur in healthy cells of older individuals. Thus, the results of this study may also help explain some of the cellular changes that accompany normal aging.