Von Hippel–Lindau disease is associated with mutations on which gene locus?
A. 1q42Answer B Von Hippel–Lindau (VHL) disease is the most common hereditary renal cancer syndrome with an incidence of 1 in 35,000 live births. VHL disease arises as a result of mutations in the Von Hippel–Lindau tumour suppressor (VHL) gene located at 3p25. Germ line mutations are present in nearly 100% of affected individuals with subsequent inactivation of the wild-type copy of the VHL gene leading to the clinical manifestation of VHL disease; clear cell renal cell carcinoma, CNS or retinal haemangioblastoma, pheochromocytoma and pancreatic cysts. RCCs are seen in up to 50% of VHL patients are often multiple and bilateral. Metastatic RCC is the most common cause of mortality in VHL patients.
The VHL protein acts as an E3 ubiquitin ligase and targets the alpha sub-unit of hypoxia inducible factor (HIF) for ubiquitin-mediated degradation. The inactivating mutations of both alleles of the VHL gene seen in VHL disease results in the constitutive over expression of HIF and its downstream targets VEGF, PDGF, TGF-a, erythropoietin, GLUT-1 and CA9, which in turn are key drivers of the oncogenic.
The fumarate hydratase gene is located at locus 1q42 and is associated with hereditary leiomyomatosis and RCC. 7q31 represents the locus for the c-met oncogene linked to hereditary papillary RCC. Tuberose sclerosis has been shown to arise as a result of mutations in the hamartin gene located at 9q34, whilst 17p11 is the locus for the folliculin gene which results in Birt– Hogg–Dubé syndrome.