Abstract
The Von Hippel-Lindau syndrome (VHLD), an inherited neoplastic syndrome predisposing to central nervous system hemangioblastoma (CNS), pheochromocytoma (PCC), renal cell carcinoma(RCC), retinal hemangioma (RA) and renal cysts, is caused by mutations or deletions of the VHL tumor-suppressor gene. To assess VHL genotype-phenotype correlations with function of pVHL a gene mutation analysis of members in a Chinese family with non-syndromic PCCs and individuals with apparently sporadic pheochromocytoma (ASP) was performed. DNA samples of 20 members from the Chinese family with non-syndromic PCCs and 41 patients with ASP were analyzed by polymerase chain reaction and direct sequencing, confirmed by Taqman probe. Three novel mutations (H125P, 623(?TTTGTtG) and R120T) were identified in the Chinese family and in 3 among 41 ASP patients. The mutations were all located in exon 2 of VHL gene encoding β-domain of pVHL. The tumor type in H125P carriers and R120T carriers was VHL type 2C. And 623(?TTTGTtG) carriers presented VHL type 2B or type 2C. VHL gene abnormalities were identified in the Chinese family with non-syndromic PCCs and patients with APS, resulting in dysfunction of pVHL. H125P and R120T could be associated with VHL type 2C, while 623(?TTTGTtG) might be linked with VHL type 2B or type 2C. Not only is the genetic analysis helpful for early diagnosis and treatment of patients with VHLD, it is also benefitial for research into VHLD pathogenesis.
Highlights
The Von Hippel-Lindau syndrome (VHLD), an inherited neoplastic syndrome predisposing to central nervous system hemangioblastoma (CNS), pheochromocytoma (PCC), renal cell carcinoma(RCC), retinal hemangioma (RA) and renal cysts, is caused by mutations or deletions of the VHL tumor-suppressor gene
VHL gene is a tumor suppressor gene mapped to chromosome locus 3p25-26, encoding two different protein VHL(pVHL30 and pVHL19) that regulates hypoxia-inducible genes, the fibronectin matrix assembly, and angiogenesis. pVHL19 with 160 amino acid protein is located in the nucleus, pVHL30 with 213 amino acid is expressed both in the nucleus and cytoplasm
There were some members of this family had H125P mutation of the VHL gene, but this proved to be a neutral variant and the levels of blood catecholamines and 24h urinary catecholamine metabolite were normal
Summary
VHL gene is a tumor suppressor gene mapped to chromosome locus 3p25-26, encoding two different protein VHL(pVHL30 and pVHL19) that regulates hypoxia-inducible genes, the fibronectin matrix assembly, and angiogenesis. pVHL19 with 160 amino acid protein is located in the nucleus, pVHL30 with 213 amino acid is expressed both in the nucleus and cytoplasm. VHL gene is a tumor suppressor gene mapped to chromosome locus 3p25-26, encoding two different protein VHL(pVHL30 and pVHL19) that regulates hypoxia-inducible genes, the fibronectin matrix assembly, and angiogenesis. The pVHL19 contains two functional subdomains: a smaller, helical α-domain, which consists of three helices (H1, H2, and H3), and a larger β-domain(residues 63-154 and residues 193-204), which forms a seven-stranded β sandwich and an α helix. These two subdomains contain different protein binding sites: The α-subunit is connected to the elongin C-binding site and the β-subunit binds to a region of HIF-α that regulates the expression of VEGF (Binderup et al, 2013). VHL gene mutations is related to the pathogenesis of VHLD (Gao et al, 2013)
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