Von Hippel - Lindau disease is a hereditary autosomal dominant syndrome characterized by the predisposition to some oncological diseases such as hemangioblastomas, pheochromocytomas, conventional renal cell carcinomas, cysts of the kidney, pancreas, and epididymis and endolymphatic sac tumors. Von Hippel - Lindau disease is a relatively rare disease with a prevalence of 1:36000 – 1:85000.
The cause of von Hippel - Lindau syndrome is a germline mutation of the VHL gene. VHL is a tumor supressor gene located on the short arm of the chromosome 3 in the region p25 -26. It is composed of three exons and encodes a protein whose main function is to regulate the response to hypoxic conditions of the organism. Under normal conditions the VHL protein in a complex with proteins elongin B, C and cullin 2 (VBC-CUL2) binds alpha subunit of the HIF protein (hypoxia inducible factor) and allows its ubiquitin-mediated degradation. Under the hypoxic conditions the HIF protein escapes the VCB-CUL2 complex and after a heterodimerization with its beta subunit activates a number angiogenic, growth and mitogenic factors such as vascular endothelial growth factor (VEGF), platelet derived growth factor beta (PDGF beta), transforming growth factor alfa (TGF alfa), erythropoetin etc..
A situation similar to the conditions under hypoxia may also occur if there is a mutation or loss of the VHL gene. VHL protein is then unable to mediate the degradation of HIF alfa protein and through its regulated genes can contribute to the processes that in the end lead to neoplasia.
However, it seems that this is not the only way by which the abnormal or missing VHL gene can contribute to the occurence of tumors. Other possible mechanisms include for example a disruption of normal cell cycle progression or affects the correct arrangement of fibronectin in extracellular matrix.
The VHL gene is analysed for the presence of mutations using PCR and direct sequencing.
VHL gene mutation is present in 100% of patients with typical symptoms of VHL syndrome (Decker, 2013).
Sequence analysis of the coding exons and exon-intron connections detects about 78% of mutations in the VHL gene listed in a publicly available version of the mutation database HGMD (The Human Gene Mutation Database).
MLPA (Multiple-Ligation Probe Amplification) analysis of the mutation in a large-scale (amplification / deletion) detects about 22% of mutations in the VHL gene listed in a publicly available version of the mutation database HGMD.
Analytical sensitivity and specificity of the sequencing: 99%.
Mutations deep in the introns and regulatory sequences are not detected. Rare polymorphisms in the location of primers or probes annealing may cause a diagnostic error.
In the case of analysis of somatic mutations sequencing mutations will not be detected, if the altered cell line is not represented by at least 20%.
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