The<unk>  is caused by mutations of the<unk><unk><unk>  tumor suppressor <unk>  gene on the short arm of chromosome 3 (3p25-26). There are over 1500 germline mutations and somatic mutations found in<unk><unk> .<unk>  is inherited in an autosomal dominant pattern. Every cell in the body has 2 copies of every gene (bar those found in the sex chromosomes, X and Y). In<unk><unk> , one copy of the<unk>  gene has a mutation and produces a faulty<unk>  protein (pVHL). However, the second copy still produces a functional protein. The condition is inherited in an autosomal dominant manner - one copy of the faulty gene is sufficient to increase the risk of developing tumours. Approximately 20% of cases of<unk><unk>  are found in individuals without a family history, known as de novo mutations. An inherited mutation of the<unk>  gene is responsible for the remaining 80 percent of cases. 30-40% of mutations in the<unk>  gene consist of 50-250kb deletion mutations that remove either part of the gene or the whole gene and flanking regions of DNA. The remaining 60-70% of<unk><unk>  is caused by the truncation of pVHL by nonsense mutations, indel mutations or splice site mutations.<unk>  protein The regulation of HIF1α by pVHL. Under normal oxygen levels, HIF1α binds pVHL through 2 hydroxylated proline residues and is polyubiquitinated by pVHL. This leads to its degradation via the proteasome. During hypoxia, the proline residues are not hydroxylated and pVHL cannot bind. HIF1α causes the transcription of genes that contain the hypoxia response element. In<unk><unk> , genetic mutations cause alterations to the pVHL protein, usually to the HIF1α binding site. The<unk>  protein (pVHL) is involved in the regulation of a protein known as hypoxia inducible factor 1α (HIF1α). This is a subunit of a heterodimeric transcription factor that at normal cellular oxygen levels is highly regulated. In normal physiological conditions, pVHL recognizes and binds to HIF1α only when oxygen is present due to the post translational hydroxylation of 2 proline residues within the HIF1α protein. pVHL is an E3 ligase that ubiquitinates HIF1α and causes its degradation by the proteasome. In low oxygen conditions or in cases of<unk><unk>  where the<unk>  gene is mutated, pVHL does not bind to HIF1α. This allows the subunit to dimerise with HIF1β and activate the transcription of a number of genes, including vascular endothelial growth factor, platelet-derived growth factor B, erythropoietin and genes involved in glucose uptake and metabolism. A new novel missense mutation in<unk>  genes c.194 C>T, c.239 G>A, c.278 G>A, c.319 C>G, c.337 C>G leading to the following variations p.Ala 65 Val, p.Gly 80 Asp, p.Gly 93 Glu, p.Gln 107 Glu, p.Gln 113 Glu in the protein contributed to renal clear cell carcinoma.
Von Hippel–Lindau disease
Mowat–Wilson syndrome
Neurofibromatosis type 4
Hurler–Scheie syndrome
Lesch–Nyhan syndrome
Neurofibromatosis type II
Neurofibromatosis type I
Stratton Parker syndrome