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A novel missense mutation (N78D) in a family with von Hippel–Lindau disease with central nervous system haemangioblastomas, pancreatic and renal cysts

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Abstract

von Hippel–Lindau (VHL) disease is a hereditary tumor syndrome caused by mutations in the VHL tumor suppressor gene. In a family with VHL, we identified a novel missense mutation (N78D), which affects a fully conserved residue in the VHL protein. Interestingly, several other missense mutations reported at same codon in the VHL protein that might be associated with a low risk of renal cell carcinoma (RCC) but not pheochromocytoma appear to be associated with a VHL type 1 phenotype. At the moment, RCC is present in none of the affected mutation carriers in the family described here. In contrast to other missense changes at codon 78, the change in our VHL family is predicted to have a mild effect on VHL function, which apparently is insufficient to cause predisposition to RCC. Our findings suggest that the risk of RCC in VHL is attributable to the severity of the amino acid substitution at this particular codon in the VHL protein.

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References

  1. Richards FM, Maher ER, Latif F, Phipps ME, Tory K, Lush M, Crossey PA, Oostra B, Gustavson KH, Green J, Turner G, Yates JRW, Linehan WM, Affara NA, Lerman M, Zbar B, Ferguson-Smith MA (1993) Detailed genetic mapping of the von Hippel–Lindau disease tumour suppressor gene. J Med Genet 30:104–107

    Article  PubMed  CAS  Google Scholar 

  2. Glenn GM, Daniel LN, Choyke P, Linehan WM, Oldfield E, Gorin MB, Hosoe S, Latif F, Weiss G, Walther M, Lerman MI, Zbar B (1991) Von Hippel–Lindau (VHL) disease: distinct phenotypes suggest more than one mutant allele at the VHL locus. Hum Genet 87:207–210

    Article  PubMed  CAS  Google Scholar 

  3. Maher ER, Yates JRW, Ferguson-Smith MA (1990) Statistical analysis of the two stage mutation model in von Hippel-Lindau disease, and in sporadic cerebellar haemangioblastoma and renal cell carcinoma. J Med Genet 27:311–314

    Article  PubMed  CAS  Google Scholar 

  4. Lonser RR, Glenn GM, Walther M, Chew EY, Libutti SK, Linehan WM, Oldfield EH (2003) von Hippel–Lindau disease. Lancet 361:2059–2067

    Article  PubMed  CAS  Google Scholar 

  5. Neumann HPH, Wiestler OD (1991) Clustering of features of von Hippel–Lindau syndrome: evidence for a complex genetic locus. Lancet 337:1052–1054

    Article  PubMed  CAS  Google Scholar 

  6. Brauch H, Kishida T, Glavac D, Chen F, Pausch F, Hofler H, Latif F, Lerman MI, Zbar B, Neumann HPH (1995) Von Hippel–Lindau (VHL) disease with pheochromocytoma in the Black Forest region of Germany: evidence for a founder effect. Hum Genet 95:551–556

    Article  PubMed  CAS  Google Scholar 

  7. Hoffman MA, Ohh M, Yang H, Klco JM, Ivan M, Kaelin WG Jr (2001) von Hippel–Lindau protein mutants linked to type 2C VHL disease preserve the ability to downregulate HIF. Hum Mol Genet 10:1019–1027

    Article  PubMed  CAS  Google Scholar 

  8. 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

    PubMed  Google Scholar 

  9. Clifford SC, Cockman ME, Smallwood AC, Mole DR, Woodward ER, Maxwell PH, Ratcliffe PJ, Maher ER (2001) Contrasting effects on HIF-1alpha regulation by disease-causing pVHL mutations correlate with patterns of tumourigenesis in von Hippel–Lindau disease. Hum Mol Genet 10(10):1029–1038

    Article  PubMed  CAS  Google Scholar 

  10. Bangiyeva V, Rosenbloom A, Alexander AE, Isanova B, Popko T, Schoenfeld AR (2009) Differences in regulation of tight junctions and cell morphology between VHL mutations from disease subtypes. BMC Cancer 14(9):229

    Article  Google Scholar 

  11. Crossey PA, Richards FM, Foster K, Green JS, Prowse A, Latif F, Lerman MI, Zbar B, Affara NA, Ferguson-Smith MA, Maher ER (1994) Identification of intragenic mutations in the von Hippel–Lindau disease tumour suppressor gene and correlation with disease phenotype. Hum Mol Genet 3(8):1303–1308

    Article  PubMed  CAS  Google Scholar 

  12. Chen F, Kishida T, Yao M, Hustad T, Glavac D, Dean M, Gnarra JR, Orcutt ML, Duh FM, Glenn G, Green J, Hsia YE, Lamiell J, Li H, Wei MH, Schmidt L, Tory K, Kuzman I, Stackhouse T, Latif F, Linehan WM, Lerman M, Zbar B (1995) Germline mutations in the von Hippel–Lindau disease tumor suppressor gene: correlations with phenotype. Hum Mutat 5:66–75

    Article  PubMed  CAS  Google Scholar 

  13. Zbar B, Kishida T, Chen F, Schmidt L, Maher ER, Richards FM, Crossey PA, Webster AR, Affara NA, Ferguson-Smith MA, Brauch H, Glavac D, Neumann HPH, Tisherman S, Mulvihill JJ, Gross D, Shuin T, Whaley J, Seizinger B, Kley N, Olschwang S, Boisson C, Richard S, Lips CHM, Linehan MW, Lerman M (1996) Germline mutations in the Von Hippel–Lindau disease (VHL) gene in families from North America, Europe, and Japan. Hum Mutat 8:348–357

    Article  PubMed  CAS  Google Scholar 

  14. Neumann HP, Bender BU (1998) Genotype-phenotype correlations in von Hippel–Lindau disease. J Intern Med 243(6):541–545

    Article  PubMed  CAS  Google Scholar 

  15. Forman JR, Worth CL, Bickerton GR, Eisen TG, Blundell TL (2009) Structural bioinformatics mutation analysis reveals genotype-phenotype correlations in von Hippel–Lindau disease and suggests molecular mechanisms of tumorigenesis. Proteins 77(1):84–96

    Article  PubMed  CAS  Google Scholar 

  16. Stebbins CE, Kaelin WG Jr, Pavletich NP (1999) Structure of the VHL-ElonginC-ElonginB complex: implications for VHL tumor suppressor function. Science 284(5413):455–461

    Article  PubMed  CAS  Google Scholar 

  17. Liu J, Nussinov R (2008) Allosteric effects in the marginally stable von Hippel–Lindau tumor suppressor protein and allostery-based rescue mutant design. Proc Natl Acad Sci USA 105(3):901–906

    Article  PubMed  CAS  Google Scholar 

  18. Hes FJ, van der Luijt RB, Janssen ALW, Zewald RA, de Jong GJ, Lenders JW, Links TP, Luyten GPM, Sijmons RH, Eussen HJ, Halley DJJ, Lips CJM, Pearson PL, van den Ouweland AMW, Majoor-Krakauer DF (2007) Frequency of Von Hippel–Lindau germline mutations in classic and non-classic Von Hippel–Lindau disease identiWed by DNA sequencing, Southern blot analysis and multiplex ligation-dependent probe ampliWcation. Clin Genet 72:122–129

    Article  PubMed  CAS  Google Scholar 

  19. Ong KR, Woodward ER, Killick P, Lim C, Macdonald F, Maher ER (2007) Genotype-phenotype correlations in von Hippel–Lindau disease. Hum Mutat 28:143–149

    Article  PubMed  CAS  Google Scholar 

  20. Gossage L, Cartwright E, Eisen T, Bycroft MA (2010) Alterations in VHL as potential biomarkers in renal-cell carcinoma. Nat Rev Clin Oncol 7(5):277–288

    Article  PubMed  CAS  Google Scholar 

  21. McNeill A, Rattenberry E, Barber R, Killick P, MacDonald F, Maher ER (2009) Genotype-phenotype correlations in VHL exon deletions. Am J Med Genet 149A:2147–2151

    Article  PubMed  CAS  Google Scholar 

  22. Gomy I, Molfetta GA, de Andrade Barreto E, Ferreira CA, Zanette DL, Casali-da-Rocha JC, Silva WA Jr (2010) Clinical and molecular characterization of Brazilian families with von Hippel–Lindau disease: a need for delineating genotype-phenotype correlation. Fam Cancer 9(4):635–642

    Article  PubMed  Google Scholar 

  23. Tavtigian SV, Deffenbaugh AM, Yin L, Judkins T, Scholl T, Samollow PB, de Silva D, Zharkikh A, Thomas A (2006) Comprehensive statistical study of 452 BRCA1 missense substitutions with classification of eight recurrent substitutions as neutral. J Med Genet 43(4):295–305

    Article  PubMed  CAS  Google Scholar 

  24. Kishida T, Stackhouse TM, Chen F, Lerman MI, Zbar B (1995) Cellular proteins that bind the von Hippel–Lindau disease gene product: mapping of binding domains and the effect of missense mutations. Cancer Res 55:4544–4548

    Google Scholar 

  25. Kanno H, Shuin T, Kondo K, Ito S, Hosaka M, Torigoe S, Fujii S, Tanaka Y, Yamamoto I, Kim I, Yao M (1996) Molecular genetic diagnosis of von Hippel–Lindau disease: analysis of five Japanese families. Jpn J Cancer Res 87:423–428

    Google Scholar 

  26. Clinical Research Group for VHL in Japan (1995) Germline mutations in the von Hippel–Lindau disease (VHL) gene in Japanese VHL. Hum Mol Genet 4:2233–2237

    Google Scholar 

  27. Bailly M, Bain C, Favrot MC, Ozturk M (1995) Somatic mutations of Von Hippel–Lindau (VHL) tumor-supressor gene in european kidney cancers. Int J Cancer 63:660–664

    Google Scholar 

  28. Maher ER, Webster AR, Richards FM, Green JS, Crossey PA, Payne SJ, Moore AT (1996) Phenotypic expression in von Hippel–Lindau disease: correlations with germline VHL gene mutations. J Med Genet 33:328–332

    Google Scholar 

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Authors and Affiliations

  1. Department of Medical Biology and Genetic, School of Medicine, Dokuz Eylül University, Izmir, Turkey

    S. Cingoz & E. Kurt

  2. Department of Medical Genetics, Section of Genome Diagnostics, UMC Utrecht, Utrecht, The Netherlands

    R. B. van der Luijt

  3. Department of Radiology, İzmir Atatürk Training and Research Hospital, Izmir, Turkey

    M. Apaydin

  4. Department of Neurosurgery, İzmir Atatürk Training and Research Hospital, Izmir, Turkey

    I. Akkol

  5. Rudolf Magnus Institute of Neuroscience, University Medical Center, Utrecht, The Netherlands

    Mihriban Heval Ozgen

  6. Department of Psychiatry, University Medical Center, Heidelberglaan 100, HP A 00.241, P.O. Box 85500, 3508 GA, Utrecht, The Netherlands

    Mihriban Heval Ozgen

Authors
  1. S. Cingoz
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  2. R. B. van der Luijt
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  3. E. Kurt
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  4. M. Apaydin
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  5. I. Akkol
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  6. Mihriban Heval Ozgen
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Correspondence to Mihriban Heval Ozgen.

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10689_2012_9586_MOESM1_ESM.doc

Supplementary Figure S1 Localization of the VHL gene mutation identified in our study. Sequence electropherograms showing c.232A >G transition resulting in substitution of Asn by Asp at codon 78 (N78D)

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Cingoz, S., van der Luijt, R.B., Kurt, E. et al. A novel missense mutation (N78D) in a family with von Hippel–Lindau disease with central nervous system haemangioblastomas, pancreatic and renal cysts. Familial Cancer 12, 111–117 (2013). https://doi.org/10.1007/s10689-012-9586-7

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  • DOI: https://doi.org/10.1007/s10689-012-9586-7

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