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 fa...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.展开更多
Von Hippel-Lindau protein(p VHL) was first identified as a tumor suppressor gene as mutations in the VHL gene predispose individuals to systemic benign or malignant tumors and cysts in many organs, including renal cel...Von Hippel-Lindau protein(p VHL) was first identified as a tumor suppressor gene as mutations in the VHL gene predispose individuals to systemic benign or malignant tumors and cysts in many organs, including renal cell carcinoma of the clear-cell type and hemangioblastoma. Although p VHL is best known to act as a component of ubiquitin protein ligase for the proteasomal degradation of hypoxia inducible factor(HIF)-α, p VHL also interacts with extracellular matrix proteins and cytoskeleton, regulating extracellular matrix assembly, cell signaling, and many other cellular functions. Recent studies suggest that p VHL contributes to many lung diseases, including pulmonary arterial hypertension, lung cancer, pulmonary fibrosis, and acute respiratory distress syndrome. Mutation or loss of function of p VHL activates HIF and induced expression of vascular endothelial growth factor, endothelin-1, and Fox M1, leading to pulmonary arterial hypertension. Loss of p VHL in lung cancer cells promotes epithelial-mesenchymal transition and cancer migration and invasion while decreasing lung cancer cell proliferation and colonization. In patients of idiopathic pulmonary fibrosis, elevated expression of p VHL induces expression of fibronectin/integrin α5β1/focal adhesion kinase signaling, resulting in fibroproliferation and fi-brosis. In alveolar epithelial cells, p VHL mediates Na, K-ATPase degradation in an HIF independent pathway, causing decreased edema clearance during hypoxia. These studies suggest that p VHL plays key roles in the pathogenesis of many lung diseases, and further investigations are warranted to elucidate the underlying molecular mechanisms.展开更多
基金This research was supported by grants from the National Natural Science Foundation of China （No. 30901487, No. 81302223, No. 81070488 and No. 81172432）, the Guangdong Natural Science Foundation （No. 10251008901000005）, and the Guangdong Province Science and Technology Project （No. 2011 B031800115, No. 2011 B032000003 and No. 20101051500032）.
文摘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.
基金Supported by Grants from Pulmonary Hypertension Association and American Lung Association to Dr.Guofei Zhou
文摘Von Hippel-Lindau protein(p VHL) was first identified as a tumor suppressor gene as mutations in the VHL gene predispose individuals to systemic benign or malignant tumors and cysts in many organs, including renal cell carcinoma of the clear-cell type and hemangioblastoma. Although p VHL is best known to act as a component of ubiquitin protein ligase for the proteasomal degradation of hypoxia inducible factor(HIF)-α, p VHL also interacts with extracellular matrix proteins and cytoskeleton, regulating extracellular matrix assembly, cell signaling, and many other cellular functions. Recent studies suggest that p VHL contributes to many lung diseases, including pulmonary arterial hypertension, lung cancer, pulmonary fibrosis, and acute respiratory distress syndrome. Mutation or loss of function of p VHL activates HIF and induced expression of vascular endothelial growth factor, endothelin-1, and Fox M1, leading to pulmonary arterial hypertension. Loss of p VHL in lung cancer cells promotes epithelial-mesenchymal transition and cancer migration and invasion while decreasing lung cancer cell proliferation and colonization. In patients of idiopathic pulmonary fibrosis, elevated expression of p VHL induces expression of fibronectin/integrin α5β1/focal adhesion kinase signaling, resulting in fibroproliferation and fi-brosis. In alveolar epithelial cells, p VHL mediates Na, K-ATPase degradation in an HIF independent pathway, causing decreased edema clearance during hypoxia. These studies suggest that p VHL plays key roles in the pathogenesis of many lung diseases, and further investigations are warranted to elucidate the underlying molecular mechanisms.
