Von Hippel–Lindau disease ( VHL ), also known as Von Hippel–Lindau syndrome , is a rare genetic disorder with multisystem involvement. It is characterized by visceral cysts and benign tumors with potential for subsequent malignant transformation. It is a type of phakomatosis that results from a mutation in the Von Hippel–Lindau tumor suppressor gene on chromosome 3p 25.3.
31-429: Signs and symptoms associated with VHL disease include headaches, problems with balance and walking, dizziness, weakness of the limbs, vision problems, and high blood pressure. Conditions associated with VHL disease include angiomatosis , hemangioblastomas , pheochromocytoma , renal cell carcinoma , pancreatic cysts ( pancreatic serous cystadenoma ), endolymphatic sac tumor , and bilateral papillary cystadenomas of
62-439: A genome . A probe that hybridizes only to a single DNA segment that has not been cut by the restriction enzyme will produce a single band on a Southern blot, whereas multiple bands will likely be observed when the probe hybridizes to several highly similar sequences (e.g., those that may be the result of sequence duplication). To improve specificity and reduce hybridization of the probe to sequences that are less than 100% identical,
93-472: A family history of developing hemangioblastomas (HB) in the central nervous system (CNS) or retinal angiomas (RA), pheo, pancreatic tumors or cysts, or epididymal cystadenomas. The second criterion applies to patients without a family history of VHL disease who present with hemangioblastomas or retinal angiomas in conjunction with other tumors such as renal cell carcinoma (RCC), pheo, pancreatic tumors or cysts, or epididymal cystadenomas. Pheo - A pheochromocytoma
124-452: A hemangioblastoma with surgery. After removal, a hemangioblastoma is unlikely to grow back. Retina angiomas - retinal capillary hemangiomas also known as retinal hemangioblastomas, occur most frequently in conjunction with von Hippel-Lindau (VHL) syndrome. These lesions are characterized by plump, but otherwise normal, retinal capillary endothelial cells with normal pericytes and basement membrane. Epidydimal cystadenomas- A cyst that grows on
155-465: A high ionic strength buffer to bind the DNA fragments to the membrane, nylon charged membranes use buffers with very low ionic strength to transfer even small fragments of DNA of about 50 bp to the membrane, usually the DNA to be transferred is separated by polyacrylamide gel. In the blotting step the most efficient method to transfer the DNA from the gel to the membrane is the vacuum transfer since it transfers
186-456: A sort of pun from Southern's name. As the label is eponymous , Southern is capitalized, as is conventional of proper nouns . The names for other blotting methods may follow this convention, by analogy. Southern invented Southern blot after combining three innovations. The first one is the restriction endonucleases, which were developed at Johns Hopkins University by Tom Kelly and Hamilton Smith . Those restriction endonucleases are used to cut
217-493: Is a non-neoplastic condition characterised by nests of proliferating capillaries arranged in a lobular pattern, displacing adjacent muscle and fat . It consists of many angiomas . They often appear in: It is a vascular malformation wherein blood vessels proliferate along with accompanying mature fat and fibrous tissue , lymphatics and sometimes nerves . They may involve skin , subcutaneous tissue , skeletal muscle and occasionally bone . Prognosis depends on
248-521: 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 VHL disease where
279-402: Is an adrenal tumor that makes and releases excess catecholamines. These tumors can cause serious health problems including stroke, heart attack, and even death. Hemangioblastomas - a hemangioblastoma is a tumor that grows in the blood vessels of your brain, spinal cord or retina. It isn’t cancerous, but it may grow and press on surrounding tissues. Usually, healthcare providers recommend removing
310-530: Is caused by mutations of the Von Hippel–Lindau tumor suppressor (VHL) gene on the short arm of chromosome 3 (3p25-26). There are over 1500 germline mutations and somatic mutations found in VHL disease. 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,
341-502: Is digested with restriction enzymes , and the resulting DNA fragments are separated by electrophoresis using an electric current to move them through a sieve-like gel or matrix, which allows smaller fragments to move faster than larger fragments. The DNA fragments are transferred out of the gel or matrix onto a solid membrane, which is then exposed to a DNA probe labeled with a radioactive, fluorescent, or chemical tag. The tag allows any DNA fragments containing complementary sequences with
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#1732802060159372-426: Is digested with either one or more than one restriction enzyme, then the DNA fragments are size-fractionated by gel electrophoresis. Before the DNA fragments are transferred to a solid membrane which is either nylon or nitrocellulose membrane they are first denatured by alkaline treatment. After the DNA fragments are immobilized on the membrane, prehybridization methods are used to reduce non-specific probe binding. Then
403-434: Is over 90% penetrance by the age of 65. Age at diagnosis varies from infancy to age 60–70 years, with an average patient age at clinical diagnosis of 26 years. The German ophthalmologist Eugen von Hippel first described angiomas in the eye in 1904. Arvid Lindau described the angiomas of the cerebellum and spine in 1927. The term Von Hippel–Lindau disease was first used in 1936; however, its use became common only in
434-743: The epididymis (men) or broad ligament of the uterus (women). Angiomatosis occurs in 37.2% of patients presenting with VHL disease and usually occurs in the retina. As a result, loss of vision is very common. However, other organs can be affected: strokes, heart attacks, and cardiovascular disease are common additional symptoms. Approximately 40% of VHL disease presents with CNS hemangioblastomas and they are present in around 60–80%. Spinal hemangioblastomas are found in 13–59% of VHL disease and are specific because 80% are found in VHL disease. Although all of these tumors are common in VHL disease, around half of cases present with only one tumor type. Most people with VHL develop symptoms in their mid-twenties. The disease
465-645: The 1970s. Some descendants of the McCoy family (involved in the Hatfield-McCoy feud of Appalachia , USA) are presumed to have VHL. In an article appearing in the Associated Press, it has been speculated by a Vanderbilt University endocrinologist that the hostility underlying the Hatfield–McCoy feud may have been partly due to the consequences of Von Hippel–Lindau disease. The article suggests that
496-404: The DNA at a specific sequence. Kenneth and Noreen Murray introduced this technique as Southern. The second innovation is the gel electrophoresis that is based on separation of mixtures of DNA, RNA, or proteins according to molecular size, which was also developed at Johns Hopkins University, by Daniel Nathans and Kathleen Danna in 1971. The third innovation is the blotting-through method which
527-701: The DNA probe sequence to be visualized within the Southern blot. The Southern blotting combines the transfer of electrophoresis -separated DNA fragments to a filter membrane in a process called blotting , and the subsequent fragment detection by probe hybridization . The method is named after the British biologist Edwin Southern , who first published it in 1975. Other blotting methods (i.e., western blot , northern blot , eastern blot , southwestern blot ) that employ similar principles, but using RNA or protein, have later been named for compass directions as
558-506: The McCoy family was predisposed to bad tempers because many of them had a pheochromocytoma that produced excess adrenaline and a tendency toward explosive tempers. An update of the Associated Press article in 2023 carries more details. Other uncommon names are: angiomatosis retinae, familial cerebello-retinal angiomatosis, cerebelloretinal hemangioblastomatosis, Hippel Disease, Hippel–Lindau syndrome, HLS, VHL, Lindau disease or retinocerebellar angiomatosis. Angiomatosis Angiomatosis
589-400: The VHL 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 VHL disease is caused by the truncation of pVHL by nonsense mutations , indel mutations or splice site mutations . The VHL protein (pVHL) is involved in the regulation of a protein known as hypoxia inducible factor 1α (HIF1α). This
620-430: 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 , platelet-derived growth factor B , erythropoietin and genes involved in glucose uptake and metabolism. 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
651-412: 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. The detection of tumours specific to VHL disease is important in the disease's diagnosis. In individuals with a family history of VHL disease, one hemangioblastoma, pheochromocytoma or renal cell carcinoma may be sufficient to make a diagnosis. As all
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#1732802060159682-402: The fragments on the membrane are hybridized with either radiolabeled or nonradioactive labeled DNA, RNA, or oligonucleotide probes that are complementary to the target DNA sequence. Then detection methods are used to visualize the target DNA. Hybridization of the probe to a specific DNA fragment on the filter membrane indicates that this fragment contains a DNA sequence that is complementary to
713-422: The hybridization parameters may be changed (for instance, by raising the hybridization temperature or lowering the salt content). Nylon membrane is more durable and has higher binding capacity to DNA fragments than nitrocellulose membrane, so the DNA fragments will be more fixed to the membrane even when the membrane is incubated in high temperatures. In addition, compared to the nitrocellulose membrane which requires
744-527: The male testes. Renal cell carcinoma- The most common type of kidney cancer. Early recognition and treatment of specific manifestations of VHL can substantially decrease complications and improve quality of life. For this reason, individuals with VHL disease are usually screened routinely for retinal angiomas, CNS hemangioblastomas, clear-cell renal carcinomas and pheochromocytomas. CNS hemangioblastomas are usually surgically removed if they are symptomatic. Photocoagulation and cryotherapy are usually used for
775-442: The probe. The transfer step of the DNA from the electrophoresis gel to a membrane permits easy binding of the labeled hybridization probe to the size-fractionated DNA. It also allows for the fixation of the target-probe hybrids, required for analysis by autoradiography or other detection methods. Southern blots performed with restriction enzyme-digested genomic DNA may be used to determine the number of sequences (e.g., gene copies) in
806-443: 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 VHL disease are found in individuals without a family history, known as de novo mutations. An inherited mutation of the VHL gene is responsible for the remaining 80 percent of cases. 30–40% of mutations in
837-427: The size and location of the tumour, untreated angiomatosis may lead to blindness and/ or permanent brain damage. Death may occur, with complications in the kidney or brain. Southern blot Southern blot is a method used for detection and quantification of a specific DNA sequence in DNA samples. This method is used in molecular biology . Briefly, purified DNA from a biological sample (such as blood or tissue)
868-405: The treatment of symptomatic retinal angiomas, although anti-angiogenic treatments may also be an option. Renal tumours may be removed by a partial nephrectomy or other techniques such as radiofrequency ablation . Belzutifan is a drug under investigation for the treatment of von Hippel–Lindau disease-associated renal cell carcinoma . VHL disease has an incidence of one in 36,000 births. There
899-622: The tumours associated with VHL disease can be found sporadically, at least two tumours must be identified to diagnose VHL disease in a person without a family history. Genetic diagnosis is also useful in VHL disease diagnosis. In hereditary VHL disease, techniques such as the Southern blot and gene sequencing can be used to analyse DNA and identify mutations. These tests can be used to screen family members of those afflicted with VHL disease; de novo cases that produce genetic mosaicism are more difficult to detect because mutations are not found in
930-450: The white blood cells that are used for genetic analysis. Von Hippel-Lindau (VHL) disease is classified into two main types based on the presence or absence of pheochromocytoma (pheo). VHL type 1 is characterized by the absence of pheo, while VHL type 2 encompasses individuals with pheo and is further divided into three subcategories: type 2A, type 2B, and type 2C. Diagnosis of VHL is guided by two key criteria. The first involves patients with
961-401: Was developed by Frederick Sanger , when he transferred RNA molecules to DEAE paper. Southern blot was invented in 1973 but it was not published until 1975. Although it was published later the technique was disseminated when Southern introduced the Southern blot technique to a scientist at Cold Spring Harbor Laboratory called Michael Mathews by drawing this technique on a paper. The genomic DNA