血友病A基因治疗的研究进展

血友病A是凝血因子VIII(FVIII)基因缺陷所致的X连锁隐性遗传性疾病,目前FVIII基因的结构已基本明确,已确认的基因突变种类繁多。基因治疗就是利用病毒载体,将正常的FVIII基因导入患者体内,并表达治疗水平的FVIII,从而实现彻底治愈血友病A。选择适合血友病A基因治疗的病毒载体,将关系到基因治疗的成功与否。该文对血友病A基因治疗中常用的病毒载体和靶细胞的研究进展作一简要综述。     

BLK基因多态性与川崎病及其临床特点的相关性

目的探讨汉族人群中BLK基因2个SNP位点rs2736340和rs2618476的多态性与川崎病(KD)以及动脉损伤的相关性。方法采取病例对照研究方法,分别选取179例KD患儿和同期182例体检正常儿童作为研究对象。利用PCRRFLP的方法测定BLK基因两个SNP位点多态性分布,并进行统计分析。结果 SNP位点(rs2736340)3种基因型(TT、CT和CC)在KD组与对照组之间分布的差异无统计学意义(P=0.093);但KD患儿T等位基因频率高于对照组,差异有统计意义(P=0.021)。SNP位点(rs2618476)3种基因型(CC、CT、TT)分布,在KD患儿与对照组之间的差异有统计学意义(P=0.021),KD组患儿CC基因型比例较高;且KD患儿C等位基因频率高于对照组,差异有统计意义(P=0.006)。KD患儿中2个SNP位点多态性均与皮疹、手足水肿以及动脉损伤无相关性,SNP(rs2618476)的多态性和口腔黏膜病变相关(P=0.018)。结论 BLK基因SNP位点(rs2736340)的T等位基因与KD相关。另一SNP位点(rs2618476)多态性与KD易感性相关;且KD患儿中该位点的多态性与口腔黏膜病变相关。     

Leigh综合征患儿核基因和线粒体基因突变的初步分析

目的探讨中国人Leigh综合征患儿的发病机制,并对已知的部分核基因和线粒体基因突变进行分析。方法对1992-2006年收集的来自我国28个省、自治区或直辖市的145例Leigh综合征患儿进行病因学分析。在排除SURF1基因和线粒体基因T8993G、T8993C、A8344G、A3243G四个位点突变后,对80例患儿的丙酮酸脱氢酶E1α亚单位基因（PDHA1）进行PCR扩增和测序分析;并在此基础上对9个线粒体DNA突变位点（G13513A、A13084T、T10158C、C11777A、T10191C、T14487C、T12706C、9537insC和T9176G）进行突变筛查。另对23例A3243G线粒体DNA突变阳性的患儿进行SURF1基因的分析。结果80例患儿中仅1例携带PDHA1基因突变,为214位点C〉T转换,导致PDHA1蛋白第27位氨基酸由精氨酸变为半胱氨酸。而64例患儿其他9个线粒体DNA突变位点筛查均为阴性。在23例携带线粒体DNAA3243G突变的患儿中,6例携带SURF1基因G604C杂合性变异。结论由于Leigh综合征病因复杂多样,使突变分析难于获得阳性结果。为缩小突变筛查的范围,明确Leigh综合征患儿的病因,亟待建立适用于临床检测应用的线粒体呼吸链酶学的测定方法。     

CDX2基因与白血病关系的研究进展

尾型同源盒基因(CDX)家族成员CDX2基因是促进胚胎发育和参与造血调控的主控基因.新近研究发现,CDX2在各型白血病中异常表达,是与白血病发生、发展和颅后相关的新的致白血病基因,可望成为白血病微小残留病检测的泛基因标志.CDX2通过调节HOX基因参与白血病转化,进一步探讨CDX2的致白血病机制及其与白血病的关系,对预...     

全面性癫癎伴高热惊厥附加症基因定位及GABRA6基因测序研究

目的　对全面癫伴高热惊厥附加症 (GEFS )家系进行基因定位 ,并对候选基因进行测序研究。方法　用连锁分析的方法对GEFS 家系进行研究 ;设计GABRA6外显子 内含子交界处全部 9对内含子引物 ,采用Sanger双脱氧链终止法 ,对GABRA6PCR测序。 结果　在 5 q34区域最大LOD值 3.815。GABRA6基因测序显示外显子 8有一C/G多态性。结论　GEFS 症致病基因在 5 q34区域取得了肯定的连锁关系。在该研究的两家系未发现GABRA6基因突变 ;所显示的单个碱基多态性对其他癫家系的连锁分析及其他癫综合征分子遗传学机制的研究均有意义     

SHANK3基因在孤独症谱系障碍发生机制中的研究进展

SHANK3蛋白是神经突触的主要支架蛋白,分布在几乎所有的兴奋性突触的突触后致密区（PSD）,参与神经转移受体和细胞骨架蛋白的相互作用,形成细胞骨架相关的信号复合物,并参与树突棘的形成和成熟。近年来,SHANK3基因的相关研究进展非常迅速。研究发现,SHANK3基因序列改变和表达调控改变与孤独症谱系障碍（ASD）有关。其中,SHANK3基因的缺失、扩增、突变均可引起SHANK3蛋白的功能障碍,从而导致ASD的各种临床症状。另外,SHANK3基因的甲基化参与其蛋白的表达调控, 其CpG岛高甲基化可导致脑中SHANK3的低表达。本文重点综述SHANK3基因近期的研究成果,并着重介绍SHANK3基因在ASD发病机制中的研究进展。     

OGG1基因的研究进展

OGG1基因是一种广泛存在于真核细胞中的管家基因,可以通过碱基切除修复途径,识别和切除DNA双链中的氧化损伤产物8-oxoG,对DNA进行修复,防止8-oxoG的致突变作用.hOGG1在1996年被成功克隆后,越来越受到人们的重视,现发现OGG1基因在肿瘤发生、衰老及退行性疾病、心肌病以及过敏性疾病等的发生发展中发挥了重要作用.通过深入研究OGG1基因的表达及其调控机制有助于探索治疗这些疾病的新方法.     

肾脏疾病与WT1基因

肾脏疾病是导致终末肾(end-stage renal disease,ESRD)的最常见原因之一.近年来的研究进展提示,在表现为蛋白尿甚至肾病综合征的肾脏疾病中,许多类型与WT1基因(Wilms′tumor 1 gene,WT1)突变有关,如孤立性激素耐药型肾病综合征(isolated steroid-resistant nephrotic syndrome,ISRNS)[1]、孤立性弥漫性系膜硬化(isolated diffuse mesangial sclerosis,IDMS)[2]、Denys-Drash综合征(Denys-Drash syndrome,DDS)[3]和Frasier综合征(Frasier syndrome,FS)[4]等.本文就WT1突变所致肾脏疾病的临床病理特点、WT1及其功能、WT1突变特点及WT1突变分析的临床意义作一简要综述.     

Loneliness in adolescence: gene × environment interactions involving the serotonin transporter gene

Background: Loneliness is assumed to peak in early adolescence and to decrease throughout middle and late adolescence, but longitudinal confirmation of this tendency is lacking. Behavioral genetic studies with twin designs have found a significant genetic component for loneliness in children and adults, but no molecular genetic studies have been conducted to reveal the functional polymorphisms involved. Methods: Associations among the serotonin transporter gene (5‐HTTLPR), sex, parental support, and loneliness were examined in a longitudinal study spanning five annual waves (N = 306). Results: Using latent growth curve modeling (LGCM), loneliness was found to be highest in early adolescence and slowly declined throughout adolescence. The 5‐HTTLPR genotype was related to the development of loneliness, in that short allele carriers remained stable in loneliness over time, whereas adolescents with the long‐long genotype decreased in loneliness. Interactions were found between maternal support and 5‐HTTLPR genotype, showing that adolescents who perceived little support from their mothers and carried a short allele were at increased risk for developing loneliness. Conclusions: Our study is the first to chart adolescent loneliness longitudinally and to examine the genetic underpinnings of loneliness. Our results contribute to a further understanding of the environmental and genetic basis of loneliness. Replication of our results is needed in both population‐based and clinical samples.     

CD40基因多态性与川崎病及其冠状动脉损伤的相关性研究

目的 探讨CD40 基因两个SNP 位点rs4810485 和rs1535045 的多态性与我国中部地区儿童川崎病（KD）以及动脉损伤遗传易感性的关系。方法 采取病例对照研究方法,分别选取184 例KD 患儿和206例正常体检儿童作为研究对象。利用PCR-RFLP 的方法测定两个SNP 位点多态性分布。结果 KD 患儿SNP位点rs4810485 的基因型（GG、GC、CC）频率及等位基因频率与正常对照组相比差异均无统计学意义（均P>0.05）;SNP 位点rs1535045 基因型（TT、TC、CC）与对照相比差异有统计学意义（P=0.011）,T 等位基因为风险因子（OR=1.592,95%CI：1.182~2.144,P=0.004）。患者中两个SNP 位点多态性均不与冠状动脉损伤相关（均P>0.05）。结论 CD40 基因SNP 位点rs4810485 与KD 无相关性, rs1535045 与KD 的易感性相关。     

EVI1与BCR/ABL基因共表达的儿童白血病临床分析

目的 研究EVI1与BCR/ABL基因共表达的儿童白血病的临床特征。方法 收集并比较分析4例EVI1与BCR/ABL基因共表达的儿童白血病以及8例BCR/ABL基因表达阳性而EVI1表达阴性的慢性粒细胞性白血病（CML）的临床资料。结果 4例EVI1与BCR/ABL基因共表达的白血病患儿初诊时2例为CML慢性期,1例为CML加速期,1例为高危急性淋巴细胞性白血病（ALL）。3例EVI1与BCR/ABL基因共表达的CML与8例BCR/ABL基因表达阳性而EVI1表达阴性CML临床特征比较无明显差异。EVI1与BCR/ABL共表达的患儿均高表达CD33、CD38。染色体分析发现4例患儿都存在t（9;22）。截止到随访日期2013年8月,3例EVI1基因表达阳性的CML患儿2例在治疗1个月或3个月后达到血液学缓解;2例BCR/ABL基因和EVI1基因均未转阴,1例EVI1基因转阴而BCR/ABL基因仍未转阴。除ALL第一疗程治疗后未达缓解,放弃治疗失访外,其余3例患儿均存活,无复发,总生存期分别为20、13、14个月。结论 EVI1与BCR/ABL融合基因共表达可存在于儿童CML和ALL中,其临床特征无特异性,其预后还需扩大样本量进一步明确。     

Dravet综合征患儿致病基因定位及GEFS+基因突变检测

目的分析海南地区Dravet综合征患儿的遗传特征。方法收集2015—2017年期间海南省18例Dravet综合征患儿及家系成员的外周血,采用PCR扩增及Sanger测序法进行SCN1A基因检测,运用连锁分析应用软件GenomeStudio进行致病基因定位分型与连锁分析;对Sanger测序法未发现SCN1A基因突变的患儿,采用多重连接依赖的探针扩增(MLPA)方法分析SCN1A基因片段缺失或重复,并筛查父母SCN1A基因,分析其突变来源。结果 18例Dravet综合征患儿及父母基因定位扫描结果完全符合亲子间的孟德尔遗传关系。SCN1A基因突变患儿可定位到5号、9号、22号染色体3个候选突变区域。其中5号染色体区域位于SNPRs 4957954至Rs 728937,在Rs 1459085处可获取到最大LOD值2. 13;9号染色体区域位于SNPRs 720974至Rs 1220087,在Rs 71332677处可获取到最大LOD值1. 92;22号染色体区域位于SNPRs 756658至Rs 713751,在Rs 374225处可获取到最大LOD值1. 91。18例患儿中,12例SCN1A基因突变,其中6例CDS区域的第5383位碱基呈现杂合变异(G→A),4例13号外显子和CDS区域的第2292位碱基纯合变异(T→C),2例SCN1A基因非编码区域碱基纯合变异(A→T)。结论海南Dravet综合征患儿的基因定位完全符合孟德尔遗传关系,推测Rs4957954至Rs728937、Rs720974至Rs1220087、及Rs756658至Rs713751区域是Dravet综合征的可能致病性区域。     

Childhood‐onset hereditary pancreatitis with mutations in the CT gene and SPINK1 gene

Hereditary pancreatitis (HP) is an autosomal‐dominant gene disorder. The affected genes have been identified as the cationic trypsinogen (CT) gene and the serine protease inhibitor Kazal type 1 (SPINK1) gene. These gene abnormalities alone, however, do not necessarily regulate the onset or severity of pancreatitis, suggesting the involvement of other gene abnormalities and environmental factors. Reported herein is the case of a 9‐year‐old boy with early‐onset HP due to mutations in the CT and SPINK1 genes. The patient had a p.R122H heterozygous mutation in the CT gene and a p.N34S heterozygous mutation in the SPINK1 gene. The father had heterozygous mutation of the SPINK1 gene, and the mother had heterozygous mutation of the CT gene, although neither had a prior history of pancreatitis. In this patient, early onset of HP was attributed to the presence of gene abnormalities in the CT and SPINK1 genes.     

Reduced gene expression of clustered ribosomal proteins in Diamond-Blackfan anemia patients without RPS19 gene mutations

Diamond-Blackfan anemia (DBA) is a rare congenital pure red cell aplasia occasionally presenting physical anomalies. Ribosomal protein S19 gene (RPS19) is one of the causative genes for DBA; however, the pathologic mechanism of erythroblastopenia and abnormal morphology has not been clarified. To assess the pathophysiology of DBA, the gene expression profile of 2 representative patients carrying no RPS19 mutations was compared with that of aplastic anemia (AA) patients, assessed by the microarray analyses. The K-mean clustering analysis revealed the significant categorization of 28 ribosomal protein (RP) genes into a small set of group (994 genes) (P=2.39E-17), all of which were expressed at lower levels in DBA than in AA patients. RPS19 was categorized into the set of low expressing genes in DBA patients. No mutations were determined in the promoter and coding sequences of top 10 RP genes expressed at the levels over 1.2 of the AA/DBA ratio, in 3 DBA patients. These results indicated that the lower expression of RP gene group, even without the mutation, was a distinctive feature of DBA from AA, although the study number was small. The reduced RP gene expression, by itself, may suggest an underlying mechanism of the constitutional anemia.