Editing Von Hippel–Lindau disease (section)

==Pathogenesis==
The disease is caused by mutations of the [[Von Hippel–Lindau tumor suppressor]] (VHL) gene on the short arm of [[Chromosome 3 (human)|chromosome 3]] (3p25-26). There are over 1500 [[germline mutation]]s and [[somatic mutation]]s found in VHL disease.<ref>{{cite journal|last1=Kondo|first1=K|title=The von Hippel–Lindau Tumor Suppressor Gene|journal=Experimental Cell Research|date=10 March 2001|volume=264|issue=1|pages=117–125|doi=10.1006/excr.2000.5139|pmid=11237528|last2=Kaelin Jr|first2=WG}}</ref><ref name="pmid20151405">{{cite journal |author=Nordstrom-O'Brien M |author2= van der Luijt RB |author3= van Rooijen E |display-authors=etal |title=Genetic analysis of von Hippel-Lindau disease |journal=Hum. Mutat. |volume=31 |issue=5 |pages=521–37 |date=May 2010 |pmid=20151405 |doi=10.1002/humu.21219|s2cid= 38910112 |doi-access=free }}</ref>

[[Image:Autosomal dominant - en.svg|thumb|right|Von Hippel–Lindau disease is inherited in an [[autosomal dominant]] pattern.]]
Every cell in the body has two copies of every gene (bar those found in the sex chromosomes, X and Y). In VHL disease, one copy of the VHL gene has a mutation and produces a faulty VHL 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.<ref>{{cite journal|last=Knudson|first=AG|title=Two genetic hits (more or less) to cancer|journal=Nature Reviews Cancer|date=Nov 2001|volume=1|issue=2|pages=157–62|pmid=11905807|doi=10.1038/35101031|s2cid=20201610}}</ref><ref name ="pmid18039096">{{cite journal|last=Kaelin|first=WG|title=Von Hippel-Lindau disease|journal=Annual Review of Pathology|year=2007|volume=2|pages=145–73|pmid=18039096|doi=10.1146/annurev.pathol.2.010506.092049}}</ref>

Approximately 20% of cases of VHL disease are found in individuals without a family history, known as ''[[Mutation|de novo]]'' mutations. An inherited mutation of the VHL gene is responsible for the remaining 80 percent of cases.<ref name = "pmid21386872"/>

30–40% of mutations in the VHL gene consist of 50-250kb [[deletion mutation]]s that remove either part of the gene or the whole gene and flanking regions of DNA. The remaining 60-70% of VHL disease is caused by the truncation of pVHL by [[nonsense mutation]]s, [[indel|indel mutation]]s or [[splice site mutation]]s.<ref name="pmid21386872"/>

===VHL protein===
[[File:HIF and pVHL.png|thumb|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 VHL disease, genetic mutations cause alterations to the pVHL protein, usually to the HIF1α binding site.]]
The VHL protein (pVHL) is involved in the regulation of a protein known as [[HIF1A|hypoxia inducible factor 1α]] (HIF1α). This is a subunit of a [[heterodimeric]] [[transcription factor]] that at normal [[Cellular respiration|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 modification|post translational]] [[hydroxylation]] of 2 [[proline]] residues within the HIF1α protein. pVHL is an [[E3 ligase]] that [[ubiquitin]]ates HIF1α and causes its degradation by the [[proteasome]]. In low oxygen conditions or in cases of VHL disease where the VHL 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]], [[PDGFRB|platelet-derived growth factor B]], [[erythropoietin]] and genes involved in glucose uptake and metabolism.<ref name ="pmid18039096"/><ref>{{cite journal|last=Bader|first=HL|author2=Hsu, T |title=Systemic VHL gene functions and the VHL disease|journal=FEBS Letters|date=June 4, 2012|volume=586|issue=11|pages=1562–9|pmid=22673568|doi=10.1016/j.febslet.2012.04.032|pmc=3372859}}</ref> A new novel missense mutation in VHL 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 {{typo help inline|reason=Should there be a space after the period or no period?|date=May 2019}} in the protein contributed to renal clear cell carcinoma.<ref>{{Cite journal | title = Novel three missense mutations observed in Von Hippel-Lindau gene in a patient reported with renal cell carcinoma | journal = [[Indian Journal of Human Genetics]] | volume = 19 | issue = 3 | pages = 373–376 |date=July 2013  | doi = 10.4103/0971-6866.120809 | pmid = 24339559 | pmc=3841571| last1 = Kumar | first1 = P. S. | last2 = Venkatesh | first2 = K. | last3 = Srikanth | first3 = L. | last4 = Sarma | first4 = P. V. | last5 = Reddy | first5 = A. R. | last6 = Subramanian | first6 = S. | last7 = Phaneendra | first7 = B. V. | doi-access = free }}</ref>