Dataset Information

Frequent Mutations of VHL Gene and the Clinical Phenotypes in the Largest Chinese Cohort With Von Hippel-Lindau Disease.

ABSTRACT: Von Hippel-Lindau (VHL) disease is a rare autosomal-dominant inherited tumor syndrome. We aimed to analyze the correlations between frequent VHL mutations and phenotypes in Chinese VHL families. We screened 540 patients from 187 unrelated Chinese VHL families for 19 frequent VHL mutations. The penetrance and mean age at onset for VHL-associated susceptible organs were calculated and compared. The overall survival of VHL patients was described with Kaplan-Meier curves. Among the 19 frequent germline mutations, there were four hotspot mutation sites (194, 481, 499, and 500). Missense mutations were the most common types of mutations (70.0%) followed by nonsense mutations (20.0%) and splicing mutations (10.0%). Due to the diversity of these mutations, the penetrance for each organ and the age at onset are distinct. Even in cases of similar mutations, variance in the penetrance and age at onset was observed. The mean age at death for the patients in this cohort was 42.4 ± 13.5 years, and variability was observed in the Kaplan-Meier curves. We present a precise summary of the phenotypes for the frequent VHL mutations in the largest Chinese VHL cohort, which provides valuable strategies for genetic counseling and clinical surveillance of VHL individuals.

SUBMITTER: Hong B

PROVIDER: S-EPMC6759728 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Frequent Mutations of VHL Gene and the Clinical Phenotypes in the Largest Chinese Cohort With Von Hippel-Lindau Disease.

Hong Baoan B Ma Kaifang K Zhou Jingcheng J Zhang Jiufeng J Wang Jiangyi J Liu Shengjie S Zhang Zhongyuan Z Cai Lin L Zhang Ning N Gong Kan K

Frontiers in genetics 20190918

Von Hippel-Lindau (VHL) disease is a rare autosomal-dominant inherited tumor syndrome. We aimed to analyze the correlations between frequent <i>VHL</i> mutations and phenotypes in Chinese VHL families. We screened 540 patients from 187 unrelated Chinese VHL families for 19 frequent VHL mutations. The penetrance and mean age at onset for VHL-associated susceptible organs were calculated and compared. The overall survival of VHL patients was described with Kaplan-Meier curves. Among the 19 frequen ...[more]

PMID: 31620170

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Project description:The von Hippel-Lindau (VHL) syndrome is a pleomorphic familial disease characterized by the development of highly vascularized tumors, such as hemangioblastomas of the central nervous system, pheochromocytomas, renal cell carcinomas, cysts and neuroendocrine tumors of the pancreas. Up to 75% of VHL patients are affected by VHL-associated pancreatic lesions; however, very few reports in the published literature have described the cellular origins and biological roles of VHL in the pancreas. Since homozygous loss of Vhl in mice resulted in embryonic lethality, this study aimed to characterize the functional significance of VHL in the pancreas by conditionally inactivating Vhl utilizing the Cre/LoxP system. Specifically, Vhl was inactivated in different pancreatic cell populations distinguished by their roles during embryonic organ development and their endocrine lineage commitment. With Cre recombinase expression directed by a glucagon promoter in alpha-cells or an insulin promoter in beta-cells, we showed that deletion of Vhl is dispensable for normal functions of the endocrine pancreas. In addition, deficiency of VHL protein (pVHL) in terminally differentiated alpha-cells or beta-cells is insufficient to induce pancreatic neuroendocrine tumorigenesis. Most significantly, we presented the first mouse model of VHL-associated pancreatic disease in mice lacking pVHL utilizing Pdx1-Cre transgenic mice to inactivate Vhl in pancreatic progenitor cells. The highly vascularized microcystic adenomas and hyperplastic islets that developed in Pdx1-Cre;Vhl f/f homozygous mice exhibited clinical features similar to VHL patients. Establishment of three different, cell-specific Vhl knockouts in the pancreas have allowed us to provide evidence suggesting that VHL is functionally important for postnatal ductal and exocrine pancreas, and that VHL-associated pancreatic lesions are likely to originate from progenitor cells, not mature endocrine cells. The novel model systems reported here will provide the basis for further functional and genetic studies to define molecular mechanisms involved in VHL-associated pancreatic diseases.

Dataset Information

Frequent Mutations of VHL Gene and the Clinical Phenotypes in the Largest Chinese Cohort With Von Hippel-Lindau Disease.

Publications

Frequent Mutations of VHL Gene and the Clinical Phenotypes in the Largest Chinese Cohort With Von Hippel-Lindau Disease.

Similar Datasets

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