摘要
精神发育迟滞(Mental Retardation,MR)又称为智力低下,是一组在发育时期内(18岁以下)以智能、情感和社会适应行为障碍为主要特征的精神障碍性疾病。精神发育迟滞不仅给患者本人及家庭带来很大的痛苦和沉重的负担,也给公共卫生、社会福利和教育服务造成巨大的压力。目前针对精神发育迟滞缺乏有效治疗方法,因此探究精神发育迟滞的致病因素是了解其发病机制和进行预防及治疗的关键。
精神发育迟滞的病因复杂,其中X连锁基因缺陷被认为是导致精神发育迟滞的重要原因之一。X连锁精神发育迟滞(X-linked mental retardation,XLMR)可以分为:综合征型精神发育迟滞(Syndromic X-linked mental retardation,MRXS)、神经肌肉型精神发育迟滞(Neuromuscular disorders)和非综合征型精神发育迟滞(non-syndromic or non-specific XLMR,MRX)。截止到目前,已经定位的X连锁精神发育迟滞基因位点数达170余个,分离到的X连锁精神发育迟滞致病基因82个。
我们在山东省遗传病调查中从山东邹城市发现了一个X连锁精神发育迟滞大家系,由于患者的部分临床症状与已报道的Smith-Fineman-Myers综合征(Smith-Fineman-Myers syndrome,SFMS,MIM309580)相似,因此该家系当时被认为是SFMS。利用连锁分析方法我们将该家系致病基因定位于Xq25.5上近10.18Mb区域。随后研究者发现SFMS是由于位于Xq13上的XNP基因突变所致。这些结果提示我们在邹城发现的XLMR家系病因不同于已经报到的SFMS,一方面可能是SFMS存在位点异质性,另一方面我们在邹城发现的XLMR家系患者可能具有不同于SFMS的临床特征。为探讨该综合征发生的分子机制,本课题发现了导致该家系患者的致病基因,并对该基因的表达模式及其转录调控、亚细胞定位和在细胞增殖中的作用进行了分析。
第一部分CUL4B基因丧失功能突变导致一种新的X连锁精神发育迟滞综合征-MRXS15
前期的连锁分析将邹城家系患者致病基因定位于Xq25.5并排除SFMS的致病基因XNP为该家系致病基因,提示邹城家系可能是一种新的X连锁精神发育迟滞综合征。因此2005年我们对该家系进行了再访,并对患者做了深入全面的临床和实验室检查。
调查发现该家系共有7名男性患者,分布在6个同胞群,未发现女性患者。所有成年患者均表现为轻度到中度精神发育迟滞,无独立生活能力。患者除表现为MR外,还具有身材矮小、短指、巨舌、足内翻、失语和单核细胞增多等特征。
为分离导致该家系患者的致病基因,我们采取候选基因分析策略对位于致病基因候选区域内的候选基因进行突变分析。在排除了9个候选基因后,发现患者CUL4B基因第9外显子的1564位核苷酸由C突变为T(c.1564C→T)。该碱基替换导致CUL4B基因编码的蛋白质第388位精氨酸密码子CGA突变成终止密码子TGA(p.R388X)。进一步分析发现该突变在家系中与疾病表型共分离;对264名无血缘关系的健康对照个体的312条染色体分析未检测到1564T,说明该突变不是多态,而是导致疾病的突变。
实时定量PCR检测发现,患者外周血白细胞CUL4B mRNA含量约为正常对照的30%,减少了70%,表明患者CUL4B基因c.1564C→T突变激活了无义介导的mRNA降解途径,导致含有突变的CUL4B mRNA降解,该突变为丧失功能突变。
与正常对照相比,女性携带者外周血CUL4B mRNA含量并未改变,提示携带突变的细胞处于选择劣势。为证实这一假设,我们对女性携带者和正常女性外周血白细胞进行了X染色体失活分析。发现女性携带者外周白血细胞表现为X染色体失活完全偏倚,所有携带CUL4B c.1564C→T突变的X染色体均失活,活性的X染色体都不携带此突变,女性携带者外周血细胞cDNA中只能检测到1564C等位基因。
综合以上研究结果,我们认为邹城家系患者是一种新的X连锁精神发育迟滞综合征MRXS15,该综合征是由于CUL4B基因丧失功能突变所致。
与此同时,英国Stratton MR领导的研究小组在对250个XLMR家系患者进行X连锁基因突变筛查,发现其中8个XLMR家系的患者是由于CUL4B基因突变所致。对比分析由CUL4B突变导致的9个来自不同种族家系患者临床表现发现,携带CUL4B基因突变的患者除精神发育迟滞外还伴有多种发育异常,提示CUL4B基因在个体的生长发育中发挥着重要作用,CUL4B基因突变是XLMR的重要原因之一。
第二部分CUL4基因表达模式分析及CUL4B转录调控机制的初步研究
遗传分析显示CUL4B基因在个体生长发育中发挥着重要作用,但对其功能几乎一无所知。Cullin家族中,CUL4A和CUL4B的同源性最高,其蛋白质的同源性高达83%。但多项研究均提示两者在生命活动中的作用机制可能有较大区别,作为认识基因功能的第一步,我们首先对CUL4A和CUL4B的表达模式进行了分析并对CUL4B的转录调控机制进行了初步的研究,取得了以下研究结果:
1.实时定量PCR分析显示,CUL4A与CUL4B在多种组织中广泛表达,但两者表达模式存在一定差别。CUL4B的mRNA在不同组织中的含量差异较大,其中胎脑和脾脏中表达水平最高,肺、肝、肾和胸腺中度表达,心脏与骨骼肌中含量最低,尤其是骨骼肌中CUL4B mRNA仅为胎脑的10%左右;与CUL4B不同,CUL4A mRNA在组织间的分布差异不很明显,其中在表达最丰的肾脏中的含量约为表达最低的骨骼肌中2倍左右。
2.利用Western blotting检测了不同组织来源的20种人细胞系中CUL4A和CUL4B的蛋白水平。结果与实时定量PCR相一致,CUL4A蛋白在各细胞系中含量差异不大;CUL4B则相差较为明显,其中在血细胞系中含量较低,而在神经细胞系中含量最高。
3.对人类CUL4B基因翻译起始点上游1kb区域的软件分析显示,该区域内存在经典的TATA-box,但距离ATG仅有50bp左右,此外该区域内也分布有CAAT、GATA保守序列以及多个如Sp1、E2F等重要的调控元件。
4.对载体P-CUL4B-952检测结果显示人类CUL4B基因翻译起始点上游-952bp区域内含有该基因的启动调控序列。进一步利用系列截短表达载体的研究发现CUL4B的转录表达调控存在组织特异性,其中在ATG上游-476bp～-452bp的区域内含有该基因的神经组织特异性转录表达调控元件。
5.突变分析显示,CUL4B ATG上游-476bp～-452bp区域内仅ELK1元件突变可导致P-CUL4B-476载体荧光素酶表达活性在SH-SY5Y细胞中明显下降,而在U87细胞与C6细胞中却并没有观察到相同的现象,提示CUL4B在神经元与胶质细胞内的转录表达调控机制存在一定差别,ELK1元件可能为CUL4B在神经元内的特异性转录表达调控元件。
第三部分CUL4的亚细胞定位及CUL4B核定位信号分析
明确蛋白质的亚细胞定位是了解蛋白质功能的基础。为此,本部分对CUL4A与CUL4B的亚细胞定位进行了分析,并在此基础上对CUL4B蛋白的核定位信号及入核机制进行了分析,得到以下结果:
1.为了分析CUL4A和CUL4B的亚细胞分布,我们将CUL4A和CUL4B的编码序列插入到EGFP标签蛋白的C端构建了EGFP-CUL4A和EGFP-CUL4B表达载体并转染不同组织来源的细胞系。结果显示外源CUL4A与CUL4B的亚细胞定位明显不同:EGFP-CUL4B主要分布在细胞核;EGFP-CUL4A则在不同细胞中的分布不同,说明CUL4A的亚细胞定位具有组织特异性。
2.为进一步证实以上观察到CUL4B的亚细胞定位结果,我们又将CUL4B编码序列插入到Myc标签蛋白的N端构建了CUL4B-Myc-His表达载体,转染细胞后观察融合蛋白在细胞内分布。与EGFP-CUL4B观察到的结果相同,CUL4B-Myc-His在不同细胞内也主要分布于细胞核。
3.为了分析CUL4B入核机制,我们分别构建了N末端和C末端缺失的CUL4B表达载体并转染HeLa细胞,结果发现CUL4B的N末端是其正确入核必需的,而C末端缺失不影响CUL4B的亚细胞定位。
4.软件分析显示CUL4B含有4个潜在的核定位信号序列,其中有三个位于N末端。为了进一步确定CUL4B功能性核定位信号,我们构建了一系列CUL4B截短表达载体并转染HeLa细胞。结果显示~(37)KKRK~(40)为CUL4B的功能性核定位信号,并且该序列在进化上高度保守。定点突变分析证实CUL4B第38位K和39位R为影响CUL4B核定位的关键氨基酸。
5.利用GST pulldown实验我们发现CUL4B能够在体外与importinα1、3、5均发生结合,并且这种结合有赖于CUL4B的NLS,提示这三种importinα蛋白均可介导CUL4B的入核。
第四部分CUL4B在细胞增殖和细胞周期调控中的作用
携带CUL4B基因突变的女性携带者表现出X染色体失活完全偏倚,携带者外周血cDNA分析只检测到正常等位基因,表明携带突变等位基因的细胞处于选择劣势,只有活性X染色体携带正常基因的细胞能有效增殖而得以保留。此外,多项研究显示CUL4A在细胞周期调控中发挥重要作用。这些结果都提示CUL4B可能参与细胞增殖和细胞周期调控。为此,我们通过过表达和低表达CUL4B,分析CUL4B对细胞增殖和细胞周期调控的影响,取得了以下结果:
1.我们首先构建了CUL4B稳定过表达的HEK293细胞并利用实时定量PCR和Western blotting实验进行了验证。MTT测定结果显示过表达CUL4B能够明显促进HEK293细胞增殖。
2.为进一步证实CUL4B在细胞增殖中的作用,我们又利用RNAi技术干扰CUL4B基因表达并建立了CUL4B稳定低表达的HeLa细胞株,发现抑制CUL4B表达可以明显抑制HeLa细胞增殖但并不影响细胞凋亡率;Brdu掺入实验也证实CUL4B表达降低导致细胞DNA合成速度减慢;细胞周期分析显示CUL4B低表达细胞的S期细胞比例明显上升,说明降低CUL4B表达引起细胞S期停滞。
3.为了探讨CUL4B影响细胞周期的分子生物学机制,我们利用Westernblotting分析方法对部分细胞周期关键调控蛋白进行检测,结果发现抑制CUL4B表达可以导致eyelin E累积。
4.亚细胞定位分析表明,CUL4B主要分布在细胞核。为了明确CUL4B入核信号在CUL4B调控细胞增殖中的作用,我们将野生型、N端缺失以及核定位信号缺失的CUL4B表达载体和CUL4A表达载体分别瞬时转染HeLa细胞,利用Brdu掺入法检测转染不同载体对细胞增殖的影响。结果发现转染CUL4A与CUL4B野生型表达载体可明显促进细胞增殖,但是转染缺失核定位信号(N末端缺失和NLS缺失)的CUL4B表达载体却不能产生类似效应,表明CUL4B正确入核是其促进细胞增殖所必需的。将以上载体转染到CUL4B低表达细胞株发现,转染野生型CUL4B能恢复CUL4B低表达对细胞增殖的抑制作用,而转染核定位信号缺失的表达载体则观察不到明显的拯救效应;分析这些细胞中cyclinE发现转染野生型CUL4B表达载体能够有效减轻HeLa细胞因CUL4B低表达而产生的cyclin E蛋白累积,而转染N基末端或NLS缺失的CUL4B表达载体却不能减少CUL4B低表达细胞中cyclin E的积累。这些拯救实验进一步证实CUL4B正确入核是其发挥调控细胞增殖和细胞周期所必需的。
综上所述,本研究首次揭示了人CUL4B基因丧失功能突变导致一种新的X连锁精神发育迟滞综合征;在此基础上我们进一步对该基因的表达模式、亚细胞定位、转录调控机制以及其在细胞增殖中的功能进行了探讨。这些研究结果为了解X连锁精神发育迟滞综合征的发病机制以及阐明CUL4B在疾病发生中的分子机制和认识CUL4B基因的功能奠定了良好的基础。
Mental retardation(MR) is characterized by sub-average cognitive functioning and deficits in social and adaptive skills,with onset under the age of 18.Because MR has a high prevalence and many MR patients need special care,it represents a major challenge and a high burden for society and families.Because of the lack of effective medical treatment for individuals with MR,identification of the etiological factors is critical for developing appropriate stragegies in the prevention,intervention and treatment of MR.
X-linked genetic defects have been considered to be one of the important causes of mental retardation.X-linked mental retardation(XLMR) conditions are subdivided into three classes based on their clinical presentations:syndromic (S-XLMR,MRXS),neuromuscular disorders and non-syndromic(NS-XLMR,MRX) forms.At present,there are more than 170 distinct MR loci mapped to the X chromosome and 82 genes have been cloned.
We identified a family with XLMR during a population survey for common hereditary diseases in Zoucheng,Shandong Province,China.Because the clinical features in this family were similar with that of Smith-Fineman-Myers syndrome (SFMS),this family was initially reported as having putative SFMS.The causative gene was mapped by linkage analysis to an interval of 10.18 Mb on Xq25.5.However, SFMS was later found to be caused by mutations in XNP,a gene located at Xq13. This suggested that either SFMS has genetic heterogeneity or this Zoucheng XLMR family represents a new syndrome that is distinct from SFMS in genetic etiology and in unrecognized phenotypes.To understand the molecular mechanisms of this disease, we identified the causative gene of Zoucheng family with XLMR and characterized its expression pattern,transcriptional regulation,subcellular localization and functional importance in cell proliferation.
PART ONE Loss of Function Mutation in CUL4B Gene Causes a New X-linked Mental Retardation Syndrome:MRXS15
The facts that the causative gene of the disease in the Zoucheng family with XLMR was mapped to Xq25 and the SFMS gene XNP was excluded as the cause of the disease suggest that cases in this family with XLMR probably represent a syndrome different from SFMS.Therefore,we revisited the family and reexamined the patients in 2005.
There are 7 affected males in 6 sibships and no female is affected in this family. All adult patients showed mild to moderate MR and led their daily lives under the care and supervision of their parents and other relatives.None of the adult patients were able to speak a single word during their lifetimes.In addition to MR,several other physical features were also observed in patients,including short stature, brachydactyly,large tongue(macroglossia),and a unique gait of walking with the toes pointing inward.Neuroimaging by magnetic resonance imaging and computed axial tomography scanning revealed no structural abnormalities.Peripheral blood tests revealed that monocyte counts were remarkably increased,whereas the total WBC counts were in the normal range.
To identify the gene responsible for this family we performed mutation analysis of candidate genes in the candidate region.After excluding the first 9 genes,we found a nonsense mutation in the 10th gene tested,CUL4B.A base substitution at 1564 in exon 9,c.1564C→T,converted a codon for arginine(CGA) to a termination codon (TGA),p.R388X.Further studies showed that this mutation cosegregated with the disease phenotype in the family.There was no 1564T allele detected among 312 X chromosomes from 264 unrelated,unaffected Chinese controls.Thus,it is unlikely that this mutation represents a polymorphism.
We next measured the mRNA levels of CUL4B in peripheral leukocytes of patients,carriers,and controls by real time PCR.We found only～30%of the mRNA,a 70%reduction,was retained in the patients when compared with the controls.These results suggest that the mRNA of CUL4B was readily eliminated in those patients by the non-sense mediated decay(NMD) mechanism and the loss of function mutation in CUL4B was the cause of MRXS15.
Interestingly,the CUL4B mRNA levels in carriers were as high as those in unaffected individuals.This was probably achieved by a selection against cells expressing the 1564T allele.To test this hypothesis,we evaluated the X-chromosome inactivation pattern in carriers and unaffected females.We found that X-chromosome inactivation was extremely skewed in all the informative carriers tested and only the wild-type allele was detected in leukocyte cDNA from those carriers.
With the identification of the CUL4B as the causative gene and the presence of some unique clinical features,we proposed that the disease in this family represents a novel syndrome(MRXS15).
These results,together with the findings of mutations of CUL4B in 8 families by Stratton et al,indicate that CUL4B is critical in cognition as well as other aspects of human development.
PART TWO Expression Pattern of CUL4 and Transcriptional Regulatory Mechanism of CUL4B
Although genetic studies showed that CUL4B plays an important role in development,little is known about the molecular function of CUL4B.CUL4 has two closely related paralogs,CUL4A and CUL4B,in mammals.Although CUL4A and CUL4B protein are 83%identical,recent studies have shown these two genes may have different functions.Therefore,in this section we investigated the expression pattern of CUL4 and characterized the transcriptional regulation of CUL4B expression by using the luciferase reporter assay.
1.Real time PCR analysis revealed that CUL4B is expressed in all tissues detected,with the highest levels in brain and spleen,moderate in lung,liver,kidney and thymus,and lowest levels in skeletal muscle,nearly 10-fold less than that in brain. CUL4A is also ubiquitously expressed.But differently from CUL4B,there is no significant difference in the expression levels among different tissues.
2.We performed Western blotting analysis of a set of 20 human cell lines. While CUL4B protein is expressed in all cell lines examined,its expression level is varied.Similar to the mRNA expression pattern in fetal human tissues,CUL4B protein is high in nervous system cell lines,but is low in all hematopoietic cell lines examined.In contrast,CUL4A is expressed at similar levels in these cell lines.
3.Computer-based analysis of the 1kb region upstream of the translational start site of human CUL4B gene revealed a putative TATA box,～50bp upstream of ATG. In addition,some other potential cis-regulatory elements such as CAAT box,GATA box,Sp1 and E2F were identified in this region.
4.P-CULB-952 showed a greater promoter activity in different cell lines including HeLa,LO2,U87 and SH-SY5Y than the promoterless luciferase vector, pGL3-basic,suggesting that the region～952bp upstream of ATG contains functional elements for the transcription of human CUL4B in different tissues.To further identify the sequence that is necessary for basal transcription of human CUL4B in different cell lines,we analyzed by reporter gcne assays various 5' deletions of the promoter. The promoter activity was drastically decreased in constructs with deletions between positions -476 and -452 in U87 and SH-SY5Y cells,but not in HeLa,HEK293 and LO2 cells,suggesting that the region from -476bp to -452bp contains nerve-specific cis-elements that arc crucial for the basal transcription of the CUL4B gene in nervous tissue.
5.Using mutagenesis analysis,we found that only the mutation of ELK1 site located in the region between -476 and -452 resulted in significantly reduced promoter activity in SH-SY5Y cells.However,this reduction of promoter activity was not observed in C6 and U87 cells,indicating that there is a difference in transcriptional regulation of CUL4B gene between neuronal cells and glial cells and ELK1 element is the neuronal specific cis-element essential for the CUL4B transcription.
PART THREE Subcellular Localization of CUL4 and Identification of a Functional NLS of CUL4B
To further understand the function of CUL4B,we investigated the subcellular localization of CUL4A and CUL4B and identified the functional NLS of CUL4B.
1.To investigate the subcellular localization of CUL4A and CUL4B,we first fused CUL4A and CUL4B cDNA containing the complete open reading frame to C-terminal end of EGFP to construct pEGFP-C1-CUL4A and pEGFP-C1-CUL4B expression vector and transiently transfected into different cell lines.The results showed that the subcellular localization of EGFP-CUL4A varies among different cell lines,while EGFP-CUL4B was exclusively localized in the nucleus in all cell lines examined.Therefore,despite their strong sequence homology,CUL4B and CUL4A have different patterns of subcellular distribution in transfected cells.
2.We next examined the subcellular localization of CUL4B-Myc-His fusion protein in which the tagged proteins Myc and His are at the C-terminal end of CUL4B by immunofluorescence using anti-Myc antibody.The results showed that like EGFP-CUL4B,CUL4B-Myc-His mainly distributed in nucleus in different cell lines.
3.We found that lacking of C-terminus did not impair the nuclear accumulation of CUL4B.In contrast,CUL4B with N-terminal end truncated was unable to accumulate in the nucleus and was exclusively observed in the cytoplasm.The N-terminal fragment of CUL4B was able to guide EGFP to the nucleus.These results indicated that N-terminus but not C-terminal region of CUL4B regulates its nuclear import.
4.We used web-based computer program PSORTⅡto predict the functional NLS in the amino acid sequence of CUL4B.According to calculations by this program,four sequences were suggested as putative NLSs of CUL4B,three in the first 100 residues and the other in the C-terminus.To determine which of the three candidate NLSs in the N-terminus are actually responsible for nuclear import of CUL4B,a series truncation mutant constructs were generated and transiently expressed in HeLa cells.The result showed that ~(37)KKRK~(40) is the functional NLS of CUL4B.Using mutation analysis,we found 38K and 39R were the key amino acids regulating the nuclear localization of CUL4B.
5.To further understand the mechanism of nuclear import of CUL4B,we performed in vitro GST pulldown experiments to investigate the ability of CUL4B to interact with importinαproteins.The results showed that all importinαs(importinα1,α3,α5) tested in this assay could interact with CUL4B in vitro in a NLS-mediated way,suggesting that these importinαs are all capable of transporting CUL4B into the nucleus in conjunction with importinβ.
PART FOUR he Role of CUL4B in Cell Proliferation and Cell Cycle Regulation
The findings that X-chromosome inactivation was extremely skewed in carriers and only the wild-type allele was detected in leukocyte cDNA from those carriers suggest that cells lacking CUL4B are impaired in proliferation and strongly selected against in vivo.In addition,previous studies have shown that CUL4A is involved in regulation of several key cell cycle regulators.These results prompted us to examine whether CUL4B also plays an important role in cell proliferation and cell cycle regulation.
1.We first evaluated the effects of CUL4B overexpression on cell proliferation by MTT assay.We found that upregulationof CUL4B expression can promote growth rate of HEK293 cells
2.Next,we employed CUL4B-specific RNAi to stably knock down endogenous CUL4B expression in HeLa cells and determined changes in cell proliferation.The results of MTT assay indicated that CUL4B depletion led to a significantly decreased growth rate of HeLa cells.Using TUNEL assay,we evaluated the effect of CUL4B down-regulation on cell apoptosis,but no difference was observed.These results suggest that the inhibition of cell growth may be mediated by cell cycle arrest.To test our hypothesis,BrdU incorporation assay and FACS analysis were employed.Consistent with MTT assay,down-regulation of CUL4B showed a significant decrease in the number of BrdU positive cells compared to the control group.Interestingly,Cell cycle distributions by FACS analysis showed the amount of cells in S phase increased about 10%in CUL4B depletion cells.Taken together,these results indicate that the inhibition of proliferation caused by constitutive silencing of CUL4B was mediated by S phase arrest.
3.To understand the molecular basis for CUL4B depletion-induced cell cycle arrest in HeLa cells,we examined the expression levels of several cell cycle regulators by Western blotting analysis.Of the proteins examined,silencing of CUL4B only led to the selective accumulation of cyclin E as compared to control cells.
4.Since CUL4B was mainly localized in nuclei,we further examined whether nuclear localization of CUL4B was required for its functions in regulating of cell proliferation.We found that an over-expression of full-length CUL4B and CUL4A significantly increased the proliferation of cells compared with untransfected cells.In contrast,expression of constructs in which the NLS or N-terminal region of CUL4B had been deleted was unable to promote cell proliferation.Rescue experiments also showed that wildtype CUL4B could restore DNA synthesis and relieve the accumulation of cyclin E protein in CUL4B-depleted HeLa cells.These data indicated that the nuclear localization of CUL4B was required for its regulation of cell proliferation.
Taken together,this study provided the first evidence of CUL4B mutation as the cause of a human disease.In addition,we analyzed the expression pattern,subcellular localization,transcriptional regulation of CUL4B and its role in cell proliferation. These results advanced our understanding of the etiology of XLMR and the functions of CUL4B in human development.
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