Rare Diseases Journal III - Von Hippel-Lindau Disease and the Nobel Prize

This occasional feature looks at “Rare Diseases”.  This designation is not an arbitrary one.  In order to qualify as a rare disease, its incidence rate must affect less than 200,000 people as established by the Congress of the United States with the Orphan Drug Act of 1983.1  In fact, the legislation, in addition to creating the definition, was also instrumental in changing the entire discussion and economy around orphan drug research in the US.  For example, during the ten years prior to its implementation, less than ten treatments were approved. However, since1983, the Office of Orphan Products Development (OOPD), which incentivizes research on what were previously untenable developmental costs, has been integral to bringing more than 400 new treatments to market. 1

There are believed to be upwards as many as 7,000 rare diseases according to the NIH.  Within their numerous centers, one, the National Center for Advancing Translational Sciences (NCATS), studies commonalities found among populations and diseases through collaborative studies.1 From that, the following programs for rare diseases have been made available:

Of course, with increased and vigorous reporting, collaborations, computer models, and even communications, the designations and prevalence of rare, and in fact, all diseases may change over time.

Von Hippel-Lindau Disease and the Nobel Prize

This Rare Disease Journal ties directly into the impetus for one researcher winning the Nobel Prize last week. Cancer researcher William G. Kaelin Jr, who along with Sir Peter J. Ratcliffe and Gregg L. Semenza, were awarded "for their discoveries of how cells sense and adapt to oxygen availability".2 Kaelin was investigating von Hippel-Lindau’s disease (VHL disease). It is typified by abnormal growth of both benign and cancerous tumors which generally begin to appear in young adulthood.3 This disease is caused by mutations to the tumor suppressor VHL gene, which are inherited in an autosomal dominant manner. (i.e., a mutation in which having only one copy of the VHL gene in each cell is sufficient to increase a person's risk of developing VHL disease.) 3. One target of the VCB-CUL2 complex is a protein called hypoxia-inducible factor 2-alpha (HIF-2α).4  This is a subunit of the larger protein complex of HIF. HIF is important that is controls several genes that are associated with cell division, formation of new blood vessels, and the production of red blood cells. Since VHL is classified as a tumor suppressor due to its likely role in the regulation and control of cell division, it was a likely research target in the hypoxia-cancer link.

Kaelin’s research showed that the VHL gene encodes a protein that prevents the onset of cancer.5

https://www.pepnet.com/res/uploads/media//800px-Paraganglioma_-_s100_-_very_high_mag.jpgVery high magnification micrograph of a paraganglioma of the duodenum, also duodenal paraganglioma. Paragangliomas may be seen a number of syndromes including von Hippel-Lindau disease. Copyright © 2011 Michael Bonert. You are free to share and adapt this image as per the CC BY-SA 3.0.

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Von Hippel-Lindau disease is a dominant inherited syndrome characterized by the predisposition to develop various kinds of benign and malignant tumors, including clear cell renal carcinomas, pheochromocytomas and hemangioblastomas of the central nervous system and retina. VHL syndrome is caused by germline mutation in the VHL tumor suppressor, and VHL tumors are associated with loss or mutation of the remaining wild-type allele. VHL has two domains: a roughly 100-residue NH2-terminal domain rich in b sheet (b-domain) and a smaller a-helical domain (a-domain), held together by two linkers and a polar interface. VHL protein is also involved in the degradation of hypoxia-inducible factor (HIF).

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Egl Nine Homolog 3 (EGLN3) belongs to the EGLN family of prolyl hydroxylases. EGLN3 catalyzes hydroxylation of the alpha subunit of hypoxia-inducible factor-alpha, which targets hypoxia-inducible factor-alpha for ubiquitination by a ubiquitin ligase complex containing the von Hippel-Lindau (VHL) tumor suppressor. EGLN3 is the most significant isozyme in limiting physiological activation of HIFs (especially HIF2A) in hypoxia. EGLN3 is activated in cardiovascular cells and Hela cells after exposure to hypoxia. In addition, EGLN3 hydroxylates PKM2 in hypoxia, thus limiting glycolysis. Under normoxia, EGLN3 hydroxylates and regulates the stability of ADRB2. EGLN3 is inhibited by polynitrogen compounds possibly by chelation to Fe2+ ions.

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Accumulation of abnormal or damaged intracellular proteins in the body can disrupt normal functions such as cell cycle regulation and inflammatory processes, as well as contribute to neurogenerative diseases such as Alzheimer’s. The ubiquitin-proteasome pathway is responsible for degrading intra-cellular protein that have been ubiquitin tagged.6 Impairment of this pathway in individuals with Alzheimer’s leads to accumulation of proteins which contributes to early onset of the disease. 7,8

It has also been recognized that inhibiting the ubiquitin-proteasome pathway may be beneficial. For example, inhibiting proteasomes in cancer cells can disrupt protein regulation, which can ultimately lead to apoptosis or programmed cell death of the malignant cells.9

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  1. https://rarediseases.info.nih.gov/diseases/pages/31/faqs-about-rare-diseases
  2. The Nobel Prize in Physiology or Medicine 2019. NobelPrize.org. Nobel Media AB 2019. Tue. 8 Oct 2019. https://www.nobelprize.org/prizes/medicine/2019/summary/
  3. https://ghr.nlm.nih.gov/gene/VHL
  4. https://www.esmo.org/Oncology-News/The-Nobel-Prize-in-Physiology-or-Medicine-2019
  5. P. Roos-Mattjus and .L Sistonen, Ann. Med., 36, 285 (2004).
  6. S.C. Upadhya and A.N. Hegde, Curr. Pharm. Des., 11, 3807 (2005).
  7. J.N. Keller, K. B. Hanni, and W.R. Markesbery, J. Neurochem., 75, 436 (2000).
  8. Y. Kudo, T. Takata, I. Ogawa et al., Clin. Cancer Res., 6, 916 (2000)

The VHL Alliance has more at their site for patients and their families.

 Other References

Frantzen C, Klasson TD, Links TP, and Giles RH. Von Hippel-Lindau Syndrome. GeneReviews. August 6, 2015; http://www.ncbi.nlm.nih.gov/books/NBK1463/.
Von Hippel-Lindau Syndrome. Genetics Home Reference. July, 2012; http://ghr.nlm.nih.gov/condition/von-hippel-lindau-syndrome.
Von Hippel-Lindau Disease. MedlinePlus. 2016; https://medlineplus.gov/vonhippellindaudisease.html.
NINDS Von Hippel-Lindau Disease (VHL) Information Page. NINDS. 2016; https://www.ninds.nih.gov/Disorders/All-Disorders/Von-Hippel-Lindau-Disease-VHL-Information-Page.


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Robert Brousseau

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Robert Brousseau, the Director of Creative Design and Media at Peptides International, has a wide range of responsibilities that include maintaining the Peptides International brand integrity and creating and implementing all materials related to marketing the company's product line. Since joining the company in 2004, he has incorporated media that now includes printed material such as product brochures and the long-running PEPNET newsletter, along with the company Website, social media, email and other outlets.  Additionally, he assists the staff with IT issues they encounter.  Bob has a background in graphic design, marketing, and advertising, in addition to project management and packaging.  He received his B.A. in Art from the University of Louisville, with additional post-graduate studies in education and design.