Abstract
Von Hippel–Lindau (VHL) is a tumor suppressor that negatively regulates the production of angiogenic factors. Mutations in the VHL gene cause VHL syndrome, which is characterized by highly vascularized tumors. Here we report a c.464T>A mutation of the VHL gene in three patients with hemangioblastoma from a Chinese family. This mutation was not reported previously and was absent in the unaffected family members. The mutation is predicted to cause Val to Glu substitution at VHL protein residue 155 in a conserved region. Previous biochemical studies demonstrated that residue Val-155 was critical for VHL protein binding to chaperonin TRiC/CCT, an essential step for proper VHL protein folding. Our finding of naturally occurring VHL V155E mutation in patients with VHL syndrome supports the functional importance of Val-155 residue in VHL protein and illustrates the diversity of VHL gene defects underlying VHL syndrome.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Clifford SC, Maher ER (2001) Von Hippel–Lindau disease: clinical and molecular perspectives. Adv Cancer Res 82:85–105
Lonser RR, Glenn GM, Walther M, Chew EY, Libutti SK, Linehan WM, Oldfield EH (2003) Von Hippel–Lindau disease. Lancet 361:2059–2067
Kaelin WG Jr (2002) Molecular basis of the VHL hereditary cancer syndrome. Nat Rev Cancer 2:673–682
Maher ER, Neumann HP, Richard S (2011) von Hippel–Lindau disease: a clinical and scientific review. Eur J Hum Genet 19:617–623
Shuin T, Yamasaki I, Tamura K, Okuda H, Furihata M, Ashida S (2006) Von Hippel–Lindau disease: molecular pathological basis, clinical criteria, genetic testing, clinical features of tumors and treatment. Jpn J Clin Oncol 36:337–343
Woodward ER, Wall K, Forsyth J, Macdonald F, Maher ER (2007) VHL mutation analysis in patients with isolated central nervous system haemangioblastoma. Brain 130:836–842
Cui Y, Wang W, Dong N, Lou J, Srinivasan DK, Cheng W, Huang X, Liu M, Fang C, Peng J, Chen S, Wu S, Liu Z, Dong L, Zhou Y, Wu Q (2012) Role of corin in trophoblast invasion and uterine spiral artery remodelling in pregnancy. Nature 484:246–250
Qi X, Chen Z, Liu D, Cen J, Gu M (2008) Expression of Dlk1 gene in myelodysplastic syndrome determined by microarray, and its effects on leukemia cells. Int J Mol Med 22:61–68
Cybulski C, Krzystolik K, Murgia A, Gorski B, Debniak T, Jakubowska A, Martella M, Kurzawski G, Prost M, Kojder I, Limon J, Nowacki P, Sagan L, Bialas B, Kaluza J, Zdunek M, Omulecka A, Jaskolski D, Kostyk E, Koraszewska-Matuszewska B, Haus O, Janiszewska H, Pecold K, Starzycka M, Slomski R, Cwirko M, Sikorski A, Gliniewicz B, Cyrylowski L, Fiszer-Maliszewska L, Gronwald J, Toloczko-Grabarek A, Zajaczek S, Lubinski J (2002) Germline mutations in the von Hippel–Lindau (VHL) gene in patients from Poland: disease presentation in patients with deletions of the entire VHL gene. J Med Genet 39:E38
Majchrzak K, Cybulski C, Bobek-Billewicz B, Majchrzak H, Lubinski J (2011) A case of carotid body paraganglioma and haemangioblastoma of the spinal cord in a patient with the N131K missense mutation in the VHL gene. Neurol Sci 32:491–496
Nordstrom-O’Brien M, van der Luijt RB, van Rooijen E, van den Ouweland AM, Majoor-Krakauer DF, Lolkema MP, van Brussel A, Voest EE, Giles RH (2010) Genetic analysis of von Hippel–Lindau disease. Hum Mutat 31:521–537
van der Harst E, de Krijger RR, Dinjens WN, Weeks LE, Bonjer HJ, Bruining HA, Lamberts SW, Koper JW (1998) Germline mutations in the vhl gene in patients presenting with phaeochromocytomas. Int J Cancer 77:337–340
Percy MJ, McMullin MF, Jowitt SN, Potter M, Treacy M, Watson WH, Lappin TR (2003) Chuvash-type congenital polycythemia in four families of Asian and Western European ancestry. Blood 102:1097–1099
Stebbins CE, Kaelin WG Jr, Pavletich NP (1999) Structure of the VHL-ElonginC-ElonginB complex: implications for VHL tumor suppressor function. Science 284:455–461
Feldman DE, Spiess C, Howard DE, Frydman J (2003) Tumorigenic mutations in VHL disrupt folding in vivo by interfering with chaperonin binding. Mol Cell 12:1213–1224
Acknowledgments
This study was supported in part by grants from of the National Science Foundation of China (81170468 and 30801125), the Natural Scientific Foundation of Jiangsu (BK2011266), Jiangsu Outstanding Medical Academic Leader Program (LJ201138) and the Priority Academic Program Development of Jiangsu Higher Education Institutions.
Conflict of interest
No conflict of interest were disclosed.
Author information
Authors and Affiliations
Corresponding author
Additional information
Yan Lu, Jun Lu and Qiang Liu contributed equally to this study.
Rights and permissions
About this article
Cite this article
Lu, Y., Lu, J., Liu, Q. et al. A c.464T>A mutation in VHL gene in a Chinese family with VHL syndrome. J Neurooncol 111, 313–318 (2013). https://doi.org/10.1007/s11060-012-1015-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11060-012-1015-0