Genetic characterization and protein stability analysis of a Chinese family with Von Hippel-Lindau disease

Background Von HippeI-Lindau disease （VHL）,a heritable autosomal dominant disease characterized by neoplasia in multiple organ systems,has rarely been reported in Asia.We genetically investigated a unique Chinese family with VHL disease and performed an analysis of the VHL protein stability.Methods Genomic deoxyribonucleic acid （DNA） extracted from peripheral blood was amplified by polymerase chain reaction （PCR） to three exons of the VHL gene in 9 members of the Chinese family with VHL disease.PCR products were directly sequenced.We estimated the effects of VHL gene mutation on the stability of pVHL,which is indicated by the free energy difference between the wild-type and the mutant protein （△△G）.Results The Chinese family was classified as VHL type 1.Three family members,including two patients and a carrier,had a T to G heterozygotic missense mutation at nucleotide 515 of the VHL gene exon 1.This missense mutation resulted in the transition from leucine to arginine in amino acid 101 of the VHL protein.There was low stability of the VHL protein （the △△G was 12.71 kcal/mol） caused by this missense mutation.Conclusions We first reported a family with this VHL gene mutation in Asia.This missense mutation is predicted to significantly reduce the stability of the VHL protein and contribute to the development of the renal cell carcinoma （RCC） phenotype displayed by this family.The genetic characterization and protein stability analysis of families with VHL disease are important for early diagnosis and prevention of the disease being passed on to their offspring.     

von Hippel-Lindau病三例并文献复习

目的:初步探讨VHL病的发病机制、诊断以及治疗。方法:回顾分析既往收治的3例VHL病人并结合文献复习。结果:3例患者中1例有家族史,另2例为多发病变,均未能全切。第1例患者鞍上无症状病变动态观察,第2例患者颈椎HB过小,动态观察,第3例患者一处病变位于颈椎腹侧,无法切除,其余病变全部切除。结论:本病诊断主要依靠MRI,治疗主要依靠手术,因累及脏器多,很难全部切除,易复发,愈后较差。     

Management of solid renal tumour associated with von Hippel-Lindau disease

Von Hippel-Lindau （VHL） disease is a rare autosomal dominant disorder caused by germ line mutations of the VHL tumour suppressor gene. it predisposes affected individuals to develop a variety of neoplasms, including haemangioblastomas of the central nervous system, retinal angiomas, renal cell carcinomas （RCCs）, pheochromocytomas and cysts of the kidneys and epididymis. Germ line VHL mutations have been found in all VHL disease families. RCC occurs in 25% to 45% of patients with VHL disease and is one of the leading causes of death.[第一段]     

Imaging manifestations of von Hippel-Lindau disease： a report of 3 cases

Von HippeI-Lindau ( VHL ) disease is an autosomal-dominant hereditary familial neoplasm syndrome characterized by development of a variety of benign and malignant tumors in multiple organ systems, such as the brain, kidney,pancreas, adrenal gland, and epididymis, with a prevalence of one in 39000 -53000.     

Clinical and Genetic Investigation of a Multi-generational Chinese Family Afflicted with Von Hippel-Lindau Disease

Background:Von Hippel-Lindau (VHL) disease is a hereditary tumor disorder caused by mutations or deletions of the VHL gene.Few studies have documented the clinical phenotype and genetic basis of the oc...     

VHL病伴发双侧肾癌3例报告并文献复习

目的 初步探讨以冯·希佩尔·林道(Von Hippel-Lindau,VHL)病并发双侧肾癌的发病特点、诊断及治疗.方法 回顾分析2007年2月-2011年6月解放军第309医院收治的3例VHL病并发双侧肾癌的患者,并结合文献复习.结果 3例中1例有家族史,先后行右侧保留肾单位手术,左侧腹腔镜下肾癌根治性切除,病理提示为透明细胞癌,术后规律血液透析,等待肾移植;另2例为多发病变,双侧肾癌伴双侧多发肾囊肿,2例均选择双侧保留肾单位手术和肾囊肿去盖术,术后病理提示为透明细胞癌,肾功能正常.结论 VHL病肾癌有独特的临床特征,不同于散发性肾癌,诊断主要依靠MRI和CT;治疗主要依靠手术,术后易复发,因累及多脏器,需要多学科给予综合治疗.     

Molecular basis of von Hippel-Lindau syndrome in Chinese patients

Background  Von Hippel-Lindau (VHL) syndrome is an autosomal dominant familial cancer syndrome predisposing the affected individuals to multiple tumours in various organs. The genetic basis of VHL in Southern Chinese is largely unknown. In this study, we characterized the mutation spectrum of VHL in nine unrelated Southern Chinese families.

Methods  Nine probands with clinical features of VHL, two symptomatic and eight asymptomatic family members were included in this study. Prenatal diagnosis was performed twice for one proband. Two probands had only isolated bilateral phaeochromocytoma. The VHL gene was screened for mutations by polymerase chain reaction, direct sequencing and multiplex ligation-dependent probe amplification (MLPA).

Results  The nine probands and the two symptomatic family members carried heterozygous germline mutations. Eight different VHL mutations were identified in the nine probands. One splicing mutation, NM_000551.2: c.463+1G>T, was novel. The other seven VHL mutations, c.233A>G [p.Asn78Ser], c.239G>T [p.Ser80Ile], c.319C>G [p.Arg107Gly], c.481C>T [p.Arg161X], c.482G>A [p.Arg161Gln], c.499C>T [p.Arg167Trp] and an exon 2 deletion, had been previously reported. Three asymptomatic family members were positive for the mutation and the other five tested negative. In prenatal diagnosis, the fetuses were positive for the mutation.

Conclusions  Genetic analysis could accurately confirm VHL syndrome in patients with isolated tumours such as sporadic phaeochromocytoma or epididymal papillary cystadenoma. Mutation detection in asymptomatic family members allows regular tumour surveillance and early intervention to improve their prognosis. DNA-based diagnosis can have an important impact on clinical management for VHL families. 

     

Bilateral Pheochromocytoma as First Presentation of von HippeI-Lindau Disease in a Chinese Family

Objective To investigate the clinical and genetic features of a Chinese family with yon Hippel- Lindau （VHL） disease revealed by bilateral pheochromocytoma. Methods The proband and other members in a Chinese family with familial pheochromocytoma were clinically evaluated and followed up. Genomic DNA extracted from the peripheral blood of 8 family members （including 3 patients） was amplified by polymerase chain reaction （PCR） and the PCR products were directly sequenced. Results The first presentation in the proband, his mother, and his sister was bilateral pheochromocytoma, and the missense mutation of 695G-A （Arg161Gln） in exon 3 of VHL gene was detected in the three patients. In the follow-up study, the proband and his mother were found to have other VHL tumors, induding retinal and cerebellar hemangioblastomas and pancreatic tumor. Neither clinical presentation of VHL disease nor gene mutation was found in other family members. Conclusion VHL disease should be suspected in some patients with familial pheochromocytoma, and VHL gene screening helps to achieve early diagnosis of the disease.     

Genetic characterization of a Chinese family with familial idiopathic pulmonary fibrosis

Background  Idiopathic pulmonary fibrosis (IPF) is a chronic inflammatory interstitial lung disease with an unknown cause. Recent studies have shown that genetic factors play an important role in the pathogenesis of IPF.

Methods  To explore the genetic background of patients with IPF, a candidate gene approach was employed to screen for mutations in seven genes among members with familial IPF in mainland of China.

Results  Within six of the candidate genes, a total of 31 point mutations were identified. Among the missense mutations, the SFTPA1 exon 6 CAG>AAG (Gln238Lys) and SFTPB exon 2 CAC>CCC (His2Pro) mutations caused changes in the physical and chemical properties of amino acids. Each sequence alteration was identified in sporadic IPF patients, control specimens (pneumonia patients and healthy persons). Genotype frequencies and allele frequencies of codon 238 in exon 6 of SFTPA1 were noted significantly higher in patients with IPF than those in other two control subjects. The computational protein structure prediction by protein homology modeling confirmed differences in three-dimensional structure between mutant SFTPA1 and original SFTPA1.     

Conclusions  Although the functions of the mutant candidate genes vary, these genes may ultimately result in damage to alveolar epithelial cells, initiating the progress of pulmonary fibrosis. In particular, while pathophysiological mechanisms need to be illustrated, the Gln238Lys missense variant of exon 6 in the SFTPA1 may have potential susceptibility in the development of IPF, which was shown in patients with sporadic IPF with a statistically higher frequency.

     

Imaging manifestations of von Hippel-Lindau disease: a report of 3 casesImaging manifestations of von Hippel-Lindau disease: a report of 3 cases

Von Hippel-Lindau (VHL) disease is an autosomal dominant here ditary familial neoplasm syndrome characte rized by development of a variety of benign and malignant tumors in multiple organ systems,such as the brain,kidney,pancreas,adrenalgland,and epididymis,with aprev a lence of one in 39000- 53000.1 4 Hallmarks of the condition in clude retinal angiomas,hem angioblastomas of the cerebellum and the spinal cord,renal cell carcinoma and cysts,and pheochrom ocytomas.In this article,we report imaging findings in three cases of VHLdisease.     

3个 VHL 综合征家族的基因检测及临床调查

目的：明确 von Hippel-Lindau 综合征(VHL 综合征)家族基因突变及临床表现特点,筛查出家族内基因突变携带者行临床筛查,综合家族发病特点行家族健康指导。方法通过流行病学调查,共3例先证者临床诊断 VHL 综合征。抽取先证者及家族自愿者外周血,应用聚合酶链反应(PCR)体外扩增得到 vhl 基因片段,通过测序得到基因信息;再对家族内具有 vhl 基因突变的携带者进行头颅 MRI、腹部 B 超等对全身多系统行临床筛查;综合家族发病特点给出家族健康指导。结果3例先证者均发现 vhl 基因发生突变,家族1中5例成员基因阳性,突变方式为外显子1 c.330C > A;家族2先证者外显子3488delC;家族3发现7例基因阳性者,突变方式为外显子1 c.233G > A。其中,家族成员1III3、3III1、3III4、3IV3确定为基因突变携带者,临床检查显示其中3例成员已发病,1III3表现为双肾多发囊肿,胰腺多发囊肿;3III1表现为胰腺多发囊肿;3III4表现为视网膜血管母细胞瘤、胰腺多发囊肿,视网膜血管母细胞瘤接受激光治疗。3IV3由于年龄较小,临床检查未见明显异常。所有基因携带者接受规范化随访。结论基因检测可早期确诊 VHL 综合征,临床上对 vhl 基因突变患者需进行严密随访,从而提高患者治疗效果、延长生存期或改善生活质量。     

VHL病并发双侧肾癌1例报告及文献复习

VHL病是一种家族性常染色体显性遗传性肿瘤病,病变可累及多个器官、表现多样,包括中枢神经系统血管母细胞瘤、内脏肿瘤和内脏多发囊肿等。对本病的了解将有助于对本病的及时诊断,避免误诊和漏诊该病。本文将报道1例并发双侧肾癌的VHL患者并结合文献阐述VHL病的临床特点、诊断方法以及治疗。     

胃食管反流病的中西医结合诊疗体会

刘万里教授主张诊疗胃食管反流病应重视中西医结合思维。在明确诊断的基础上，对胃食管反流病治疗采取分期疗法，发作期以快速愈合炎症、缓解控制症状为治疗目标，此阶段以西药为主、中药为辅；缓解期主要是巩固疗效、减少复发，中药为主、西药为辅。针对难治性胃食管反流病，刘万里教授强调优化诊疗方案的重要性，找到中医干预胃食管反流病的切入点，发挥中医药“治病求本”“辨证论治”等特色优势，可提高胃食管反流病的临床疗效，显著减少复发率。     

遗传性内分泌代谢性疾病的基因和临床研究

遗传性内分泌代谢疾病是内分泌代谢疾病中相当重要的一组疾病,临床表现复杂多变,诊治困难。项目组针对目前该领域存在的问题,通过提出并逐步完善遗传性内分泌疾病的三类十种分类体系,建立科学完备的程式化基因诊断平台,并在国内外首次构建病种丰富、管理规范的遗传家系库,对保护遗传资源、探讨疾病发生机制及高危人群预防均有重要意义。研究成果获2008年国家科技进步二等奖、2006年上海市科技进步一等奖、2006年上海医学科技一等奖和2006年中华医学科技二等奖。     

D二聚体与脑血管病关系的研究

目的　探讨D二聚体(DDimer,DD)与脑血管病的关系。方法　采用ELISA法,分别采取观察对象空腹静脉血2ml,脑血管病患者为发病后1周内采血,定量检测急性脑血管病及高血压、脑动脉硬化患者血浆DD含量。结果　短暂性脑缺血发作(TIA)、脑梗塞及蛛网膜下腔出血(SAH)与正常对照组相比有显著性差异(P<005),高血压、脑动脉硬化及脑出血与正常对照组相比无显著性差异(P>005),SAH血浆DD含量与各组相比有显著性差异(P>005),SAH血浆DD含量与各组相比有显著性差异(P<005),其他各组两两比较无显著性差异(P>005)。结论　测定DD对急性脑血管病的诊断有价值,对其鉴别诊断无参考意义。     

Correlation of red cell distribution width with the severity of coronary artery disease: a large Chinese cohort study from a single center

Background It has been reported that increased red blood cell width (RDW) is a marker associated with the presence and adverse outcomes of various cardiovascular diseases.The aim of the present study w...     

中国汉族人群Semaphorin 5A基因多态性与帕金森病易感性的关联研究

目的 探讨Semaphorin 5A(SEMA5A)基因多态性与帕金森病(PD)易感性的关系.方法 选择244例帕金森病患者和174名正常对照,利用聚合酶链式反应-限制性片段长度多态性(PCR-RFLP)方法检测中国汉族人群中SEMA5A基因的两个基因多态性位点(SNP)和帕金森病易感性的关系,并用基因测序验证结果.结果 SEMA5A基因的多态性位点rs7702187和rs3798097(rs7702187:OR(基因型AT)=0.95,95%CI 0.61～1.48,OR(基因型AA)=1.84,95% CI 0.85～3.99,OR(基因型AT+AA)=1.21,95%CI 0.82～1.77,P>0.05;rs3798097:OR(基因型CT)=1.06,95% CI 0.62～1.79,OR(基因型TT)=0.72,95% CI 0.10～5.18,OR(基因型CT+TT)=1.01,95%CI 0.62～1.67,P>0.05)与PD易感性之间无关联性;与最常见的单倍型TC相比,AC单倍型,TT单倍型均与PD易感性无关(AC单倍型:OR=1.19,95%CI 0.84～1.69,P>0.05;TT单倍型:OR=0.99,95% CI 0.59～1.70,P>0.05).结论 中国汉族人群中,SEMA5A基因与PD发病无相关性.     

淋巴结内Castleman病临床病理分析

目的：探讨Castleman病的临床病理学特征及诊断、鉴别诊断。方法：通过组织学、免疫组化方法对5例Castleman病进行分析研究,并结合文献加以讨论。结果：3例为透明血管型,表现为增生的淋巴结内散在分布大型的淋巴滤泡,滤泡中心血管壁玻璃样变,其内可见核成空泡状的滤泡树突状细胞,外套层明显增厚,小淋巴细胞呈同心圆状包绕于血管周围,形成特征性的“洋葱皮”样同心圆结构。2例浆细胞型,特点是滤泡内的毛细血管玻璃样变性和“洋葱皮”样改变不明显,滤泡间可见粉染的无定型的嗜酸性物质沉积,并有大量成熟浆细胞弥漫增生。结论：Castleman病是一种特殊类型的淋巴结增生性疾病,诊断时要与反应性滤泡性增生、淋巴瘤等进行鉴别,并注意是否发生淋巴瘤等恶性转化。     

慢性阻塞性肺病合并支气管扩张的临床研究

目的探讨慢性阻塞性肺病合并支气管扩张的临床特点及诊断。方法回顾性分析本院5年来诊断的61例慢性阻塞性肺病合并支气管扩张的患者的临床表现、影像学特点、肺功能特点。结果以慢性阻塞性肺病首先表现者(A组)多为高龄患者,吸烟者多、吸烟量大、时间长,高分辨率CT示支气管扩张部位多在肺气肿及肺大泡周围、双上肺多见,肺功能以中重度阻塞性通气障碍多见,弥散功能明显下降;以支气管扩张首先表现者(B组)发病年龄稍小,吸烟者少,咳大量黄脓痰、咯血者多,胸部CT示支气管扩张影像学表现典型,以下肺居多,可见肺气肿和肺大泡,肺功能呈轻中度阻塞性或混合性通气功能障碍。结论慢性阻塞性肺病和支气管扩张在临床上不易鉴别,但确可同时存在,肺功能检查和高分辨率CT检查可协助临床诊断。