Zhang Jingyao, Ma Jie, Du Xiaoyun, Wu Dapeng, Ai Hong, Bai Jigang, Dong Shunbin, Yang Qinling, Qu Kai, Lyu Yi, Valenzuela Robert K, Liu Chang
Department of Hepatobiliary Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.
Chin Med J (Engl). 2015 Jan 5;128(1):32-8. doi: 10.4103/0366-6999.147802.
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 occurrence of VHL disease in China. This study armed to present clinical and genetic analyses of VHL within a five-generation VHL family from Northwestern China, and summarize the VHL mutations and clinical characteristics of Chinese families with VHL according to previous studies.
An epidemiological investigation of family members was done to collect the general information. A retrospective study of clinical VHL cases was launched to collect the relative clinical data. Genetic linkage and haplotype analysis were used to make sure the linkage of VHL to disease in this family. The VHL gene screening was performed by directly analyzing DNA sequence output. At last, we summarized the VHL gene mutation in China by the literature review.
A five-generation North-western Chinese family afflicted with VHL disease was traced in this research. The family consisted of 38 living family members, of whom nine were affected. The individuals afflicted with VHL exhibited multi-organ tumors that included pheochromocytomas (8), central nervous system hemangioblastomas (3), pancreatic endocrine tumors (2), pancreatic cysts (3), renal cysts (4), and paragangliomas (2). A linkage analysis resulted in a high maximal LOD score of 8.26 (theta = 0.0) for the marker D3S1263, which is in the same chromosome region as VHL. Sequence analysis resulted in the identification of a functional C>T transition mutation (c. 499 C>T, p.R167W) located in exon 3 of the 167 th codon of VHL. All affected individuals shared this mutation, whereas the unaffected family members and an additional 100 unrelated healthy individuals did not. To date, 49 mutations have been associated with this disease in Chinese populations. The most frequent VHL mutations in China are p.S65 W, p.N78 S, p.R161Q and p.R167 W.
The results supported the notion that the genomic sequence that corresponds to the 167 th residue of VHL is a mutational hotspot. Further research is needed to clarify the molecular role of VHL in the development of organ-specific tumors.
冯·希佩尔-林道（VHL）病是一种由VHL基因突变或缺失引起的遗传性肿瘤疾病。在中国，很少有研究记录VHL病发生的临床表型和遗传基础。本研究旨在对来自中国西北部的一个五代VHL家系进行VHL的临床和遗传分析，并根据以往研究总结中国VHL家系的VHL突变和临床特征。
对家庭成员进行流行病学调查以收集一般信息。开展对VHL临床病例的回顾性研究以收集相关临床数据。采用遗传连锁和单倍型分析来确定该家系中VHL与疾病的连锁关系。通过直接分析DNA序列输出进行VHL基因筛查。最后，通过文献回顾总结中国的VHL基因突变情况。
本研究追踪到一个患有VHL病的中国西北部五代家系。该家系由38名在世家庭成员组成，其中9人患病。患有VHL的个体表现出多器官肿瘤，包括嗜铬细胞瘤（8例）、中枢神经系统血管母细胞瘤（3例）、胰腺内分泌肿瘤（2例）、胰腺囊肿（3例）、肾囊肿（4例）和副神经节瘤（2例）。连锁分析结果显示，与VHL位于同一染色体区域的标记D3S1263的最大LOD值高达8.26（θ = 0.0）。序列分析确定了位于VHL第167位密码子外显子3中的一个功能性C>T转换突变（c.499 C>T，p.R167W）。所有患病个体都有此突变，而未患病的家庭成员和另外100名无关健康个体则没有。迄今为止，在中国人群中已有49种突变与该病相关。中国最常见的VHL突变是p.S65W、p.N78S、p.R161Q和p.R167W。
结果支持了与VHL第167位残基对应的基因组序列是一个突变热点的观点。需要进一步研究以阐明VHL在器官特异性肿瘤发生中的分子作用。
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