中国人Wolfram综合征WFS1基因的新突变

目的研究一个中国人Wolfram综合征患者家系中的WFS1基因突变情况。方法应用PCR-DNA直接测序对一个Wolfram综合征患者及家系成员的WFS1基因8个外显子及其侧翼内含子进行突变筛查;采用生物信息学方法对突变蛋白的结构与功能进行估测。结果发现外显子8第417位密码子发生缺失突变,即F417del。先证者为突变纯合子,其父母为姑表亲近亲结婚,均为突变杂合子。F417del突变位于跨膜区,失去了一个非极性氨基酸。生物信息学分析提示该突变可引起跨膜区二级结构改变并使突变蛋白疏水性下降。结论本研究发现的F417del突变是一个尚未报道过的Wolfram综合征新突变。     

Wolfram综合征1例报道并文献复习

目的:报道1例Wolfram综合征患者的诊断过程,以提高对此病的认识。方法:对某院收治的1例Wolfram综合征患者的临床表现、实验室检查、影像学检查及诊断过程进行分析,结合文献加以讨论。结果:患者以糖尿病为首发症状,后逐渐出现视力下降、尿崩症及视神经萎缩。患者弟弟8岁,诊断为糖尿病4年,尚未出现其他系统损害。患者误诊为糖尿病多年,姐弟基因结果均显示存在4号染色体上WFS1基因的第8号外显子的复合杂合变异,父母均为杂合,最终诊断为Wolfram综合征1型。结论:Wolfram综合征临床罕见,表现复杂多样,易导致漏诊。对合并视力下降的糖尿病患者,如果血糖控制基本正常,仍有多饮、多尿表现者,需警惕Wolfram综合征,应尽早进行基因检测明确诊断,早期干预,减缓病情进展。     

SURF1基因两个新突变致Leigh综合征1例

目的研究1例因常染色体Surfeit 1（SURF1）基因2个新突变所致Leigh综合征女童的临床及其突变特点.方法患儿为第一胎,生后运动发育落后,4岁时出现肢体震颤,进行性加重,伴运动倒退.4岁6个月来院时不能独站,左侧肢体痉挛性瘫痪,血乳酸、丙酮酸增高,腓肠肌活检未见异常.脑MRI显示双侧基底节、小脑脚上交叉多发性软化灶,符合Leigh综合征诊断.患者曾口服安坦、维生素B1等药物无效,12岁死于肺炎、呼吸衰竭.本研究运用聚合酶链式反应扩增SURF1基因的9个外显子序列,对患儿及103名正常人的外周血白细胞DNA进行正反向序列测定检测突变.结果患者线粒体基因筛查未见异常,SURF1基因测序发现了分别位于内含子3的240＋1G＞C剪切位点突变和外显子6的574C＞G错义突变两个杂合性新突变.结论细胞色素C氧化酶缺陷是Leigh综合征的常见原因,本研究通过对1例中国Leigh综合征患者的SURF1基因分析,首次发现了240＋1G＞C和574C＞G两个新突变,不仅明确了患者病因,并将进一步充实人类Leigh综合征致病基因库.     

AKT1基因嵌合突变致Proteus综合征一例报告并文献复习

目的 对1例AKT1基因嵌合突变致Proteus综合征患儿的临床资料及遗传学特点进行分析并复习相关文献.方法 对2015年6月北京协和医院儿科收治的1例Proteus综合征患儿的临床资料及基因检测结果进行分析,并以"Proteus syndrome""Proteus综合征"为检索词,分别检索Pubmed数据库及中文数据...     

WFS1基因在糖尿病发病机制中的研究进展

Wolfram syndrome 1(WFS1)基因编码内质网的跨膜糖蛋白Wolframin,该蛋白在膜的运输、分泌、加工及调控内质网钙稳态等方面有重要的生理功能。Wolfram综合征是由WFS1基因突变引起的常染色体隐性遗传病,以青少年糖尿病和视神经萎缩为主要症状。除特殊类型糖尿病外,WFS1基因的单核苷酸多态性还与1型和2型糖尿病发病相关。WFS1基因很可能是通过影响未折叠蛋白反应、内质网钙稳态等内质网应激相关通路以及胰岛素分泌颗粒等多种途径而影响糖尿病的发生。     

中国人遗传性长QT综合征KCNQ1和KCNH2基因新突变

目的:遗传性长QT综合征(LQTS)是一种常染色体遗传性心脏病.特征性表现为心电图上QTc延长及尖端扭转性室性心动过速(TdP)导致的晕厥和猝死.近年来随着分子遗传学的发展已明确遗传性LQTS是由于编码离子通道的基因突变造成的,包括编码钠离子通道的基因SCN5A和编码钾离子通道亚单位的基因KCNQ1, KCNH2, KCNE1, KCNE2,和 KCNJ2.目前,中国人LQTS基因突变的报道较少,本研究目的是找到中国LQTS基因突变.方法:应用聚合酶链反应和测序分析,对来自中国14个省、市、自治区的31个遗传性LQTS家系筛查了最常见的2个LQTS致病基因KCNQ1 和 KCNH2.结果:发现了2个KCNQ1 新突变:S5跨膜片段的S277L 和孔区的G306V ;3个KCNH2 新突变:跨膜片段S1的L413P、跨膜片段S5的L559H和发生于跨膜片段S3的L520V.KCNH2 L413P 和L559H突变患者的ECG T波为双峰;KCNQ1 S277L和G306V 突变患者的ECG T 波高尖.结论:本研究发现的突变点丰富了LQTS离子通道突变的基因库资料.本研究的中国LQTS患者的突变率KCNQ1 (6.5%) 和KCNH2 (10%)低于北美和欧洲患者.     

7例Goldenhar 综合征患者SALL1和TCOF1基因突变检测

目的探索Goldenhar综合征的致病原因。方法采集7例患者及其父母和正常同胞的详细临床资料和基因组DNA,PCR扩增SALL1和TCOF1的全部外显子及部分内含子,用直接双向测序、Blast比对进行突变分析。结果在SALL1发现了2个多态数据库已报道的单核苷酸多态;在TCOF1基因中发现了7个序列变异,其中6个已被报道为多态,1个为新发现的内含子突变。所有序列变异都存在于患者的正常亲属中,与疾病表型无共分离现象。结论排除了SALL1和TCOF1外显子突变导致此7例患者颜面畸形的可能性。     

WFS1突变致聋家系的鉴定及斑马鱼同源基因时空表达谱分析

目的：对2个遗传性耳聋家系进行分子病因学鉴定,并应用斑马鱼对致聋基因WFS1进行初步功能分析。方法：利用靶向捕获测序技术,对2个家系进行外显子测序分析,确定候选致病基因。生物信息学预测人WFS1基因的功能以及模式生物斑马鱼与人类WFS1基因的同源性;采用整胚原位杂交和定量PCR法分析斑马鱼wfs1a和wfs1b的时空表达特征。结果：外显子测序及家系遗传共分离分析确定WFS1基因c.2036~2038delAGG（p.680delE）和c.1957C>T（p.653R>C）突变分别是2个家系的分子病因。定量PCR和全胚原位杂交结果显示斑马鱼wfs1a和wfs1b在胚胎发育不同时期呈现不同的时空表达特征。生物信息学分析提示wfs1b与人WFS1基因的进化距离更近,同源性更高。结论：2个遗传性耳聋家系均由WFS1突变所致,拓展了遗传性耳聋的基因突变谱。斑马鱼胚胎发育过程中wfs1a和wfs1b具有明显的时空表达特异性,wfs1b是人类WFS1的直系同源基因。研究结果既为耳聋分子诊断提供了支持,也为后续深入研究WFS1的突变致聋机制奠定了基础。     

Spectrum of NSD1 gene mutations in southern Chinese patients with Sotos syndrome

Sotossyndrome(MIM117550),alsoknownascerebralgigantism,wasfirstdescribedin1964.1Sincethen,hundredsofcaseshavebeenreported.2,3It isadiseasewiththecombinationofsomaticovergrowth, advancedboneage,characteristicfacialappearanceand developmentaldelay.2 OvergrowthinSotossyndromeisusuallyevidentsince birth.Allthegrowthparametersareincreased,withthe headsizeremaininglargewhileheightandweightshowing atendencytonormalizewithadvancingage.The characteristicfacialfeaturesarehighprominentforehead, hypertel…     

Two novel STK11 mutations in three Chinese families with Peutz-Jeghers syndrome

Background Peutz-Jeghers syndrome (PJS) is an autosomal dominantly inherited disease. STK11/LKB1 gene germline mutations have been identified as responsible for PJS. In our study, we investigated the molecular basis of PJS and evaluated correlation between the STK11 mutations and the Chinese population.Methods We collected three pedigrees of PJS and screened the 9 exons and their flanking intronic sequences of STK11/LKB1 gene in the probands and normal individuals in the families using polymerase chain reaction (PCR) and direct sequencing.Results Sequencing of the STK11 gene in the probands of 3 families revealed two novel mutations (c180C→G and c998-1002delGCAGC) in exon 1 and exon 8, respectively. The mutation of c180C→G resulted in a premature termination codon. The other mutation, a deletion of five nucleotides (998-1002delGCAGC) in exon 8, predicted to generate a translational frameshift and a termination at codon 1070.Conclusions The growing number of mutations in PJS pedigrees suggests the molecular basis of PJS. STK11 gene mutation can be detected in most patients with PJS.     

表皮松解性角化过度鱼鳞病COL7A1基因突变研究

目的探讨一个表皮松解性角化过度鱼鳞病家系基因的突变。方法提取表皮松解性角化过度鱼鳞病患者及家族成员的基因组DNA，采用PCR扩增COL7A1基因所有的外显子及其邻近的剪切点并进行双向直接测序，用PCR检测突变位点从而进一步确定家系的致病原因。结果发现患者COL7A1基因的一条等位基因第2号外显子上存在S48P的错义突变，而另一条等位基因第27号外显子上存在3625del 11缺失突变，造成编码区阅读框架的移位，最终导致蛋白终止密码（PTC）的生产。结论COL7A1基因的缺失突变和锆义突变引起该患者临床症状的特异突变。     

A novel mutation in TPRS1 gene caused tricho-rhino-phalangeal syndrome in a Chinese patient with severe osteoporosis

Tricho-rhino-phalangeal syndrome (TRPS) was first reported in 1966. Although mutation of TRPS1 gene is considered to be responsible for the syndromes in 2000, investigation of bone metabolism and changes of serum insulin-like growth factor (IGF)-1 level in this kind of patients is rare. Here, we report a patient with TRPS I (MIM 190350) presenting a novel mutation (1096insA) and abnormal changes of severe osteoporosis as well as low serum IGF-I level.

     

中国北方一马凡氏综合征家系致病基因突变研究

目的研究确定我国北方一马凡氏综合征(MFS)家系致病基因突变位点。方法对马凡氏综合征一家系进行临床研究和系谱分析。采集家系中3例患者和3例健康成员的静脉血,提取基因组DNA。应用聚合酶链反应(PCR)扩增马凡氏综合征致病基因原纤维蛋白1(FBN1)基因外显子及外显子-内含子接头处,直接测序确定致病的基因突变。结果马凡氏综合征患者的FBN1基因外显子6发生了错义突变,cDNA 640位的鸟嘌呤被腺嘌呤取代(G640A);对应的甘氨酸改变为丝氨酸。突变后EagⅠ内切酶位点消失。该突变在家系中表现为与疾病共分离。结论 FBN1基因突变G640A是该马凡氏综合征家系的致病基因突变。     

一个中国Gilbert综合征家系的临床和遗传学特征分析

目的 通过对1个中国Gilbert综合征家系成员临床特征分析,结合致病基因尿苷二磷酸葡萄糖醛酸转移酶1A1(UGT1A1)基因已知突变位点鉴定,了解该病临床发病特点和分子遗传学基础.方法 在长期追踪先证者基础上,抽取先证者及其家系成员外周血,进行肝脏生化学、病原学和UGT1A1基因突变位点检测,排除相关疾病,PCR扩增启动子和外显子常见突变位点,产物直接测序鉴定基因型.结果 在该家系中,检测到3个突变位点:c.-3279T＞G、TA插入和Gly71Arg,并且C.-3279T＞G和TA插入存在连锁不平衡,其中4例患者中3例为杂合突变,1例为纯合突变,胆红素水平与UGT1A1基因型和表型相关.结论 c.-3279T＞G、TA插入和Gly71Arg突变可能与中国人群Gilbert综合征发生相关,该家系基本符合常染色体隐性遗传方式.     

Identification of a novel lethal fibrillin-1 gene mutation in a Chinese Marfan family and correlation of 3’ fibrillin-1 gene mutations with phenotype

Background Mutations in the fibrillin-1 gene have been identified in patients with Marfan syndrome （MFS）. This study aimed to identify the molecular defects in the fibrillin-1 gene in a Chinese family with Marfan syndrome, accompanied by aortic aneu rysms/dissection. Methods Two patients and one non-carrier in the family underwent complete physical, ophthalmic, and cardiovascular examinations. Genomic DNA was extracted from leukocytes of venous blood of these individuals in the family as well as 50 healthy normal controls. Polymerase chain reaction amplification and direct sequencing of all 65 coding exons of fibrillin-1 gene were analyzed. Results We found a novel mutation （c.8547T〉G, p.Tyr2849X） in exon 65 of fibrillin-1 gene in a Chinese proband with Marfan syndrome, accompanied by aortic aneurysms/dissection. Sudden death at a young age of affected members was seen due to aortic aneurysms/dissection. By evaluating genotype-phenotype correlations of patients with mutations in the 3＇ end of fibrillin-1 gene （exons 64 and 65）, we also found that the presence of nonsense mutations occurring in exons 64 and 65 appeared to be an indicator of early-onset aortic risk and sudden death. Conclusions These results expand the mutation spectrum of fibrillin-1 gene and help in the study of the molecular pathogenesis of Marfan syndrome, indicating that mutations occurring in the 3＇ end of fibrillin-1 gene may play an independent functional role in the pathogenesis of Marfan syndrome.     

A novel nonsense mutation in BBS4 gene identified in a Chinese family with Bardet-Biedl syndrome

Background Bardet-Biedl syndrome (BBS) is a genetically heterogeneous disease, and information about BBS in Chinese populations is very limited. The purpose of the present study was to determine the genetic cause of BBS in a Chinese Han family.

Methods Clinical data were recorded for the 4-year-old female proband and the available family members. The proband was screened for mutation by Sanger sequencing for a total of 142 exons of the 12 BBS-causing genes (BBS1-BBS12). The variants detected in the proband were further confirmed in the other family members.

Results We identified a novel homozygous nonsense mutation (c.70A>T, p.K24X) in the BBS4 gene exon 2 in the proband. Such mutant allele was predicted to cause a premature truncation in the N-terminal of the BBS4 protein, and probably induced the nonsense-mediated decay of BBS4 messenger RNAs. The proband’s parents and brother were heterozygous for the nonsense mutant allele. It was absent in 50 Chinese control subjects. An additional rare heterozygous missense single nucleotide polymorphism (SNP) named rs200718870 in BBS10 gene was also detected in the proband, her father and her brother. Some manifestations of the proband including atypical retinitis pigmentosa, choroidal sclerosis, high myopia, and early onset of obesity might be associated with this mutation in BBS4 gene. The proband’s father also reported surgical removal of an extra finger during childhood.

Conclusions The present study described a novel nonsense mutation in BBS4 gene in a Chinese family. This homozygous mutation was predicted to completely abolish the synthesis of the BBS4 protein. We also detected a rare heterozygous missense SNP in BBS10 gene in the family, but did not ?nd sufficient evidence to support the triallelic inheritance.