Human Genetics

, Volume 95, Issue 6, pp 681–686

Identification of a candidate missense mutation in a family with von Willebrand disease type IIC

  • Reinhard Schneppenheim
  • Kathy B. Thomas
  • Sonja Krey
  • Ulrich Budde
  • Ursula Jessat
  • Anton H. Sutor
  • Barbara Zieger
Original Investigation

Abstract

A screening project to identify candidate molecular defects causing von Willebrand disease type IIC (VWD IIC) in a German family was carried out using polymerase chain reaction (PCR) amplification of all 52 exons of the von Willebrand factor (VWF) gene, subsequent electrophoresis of single and double stranded DNA and direct sequencing of PCR products with aberrant electrophoretic patterns. Only one candidate mutation, G550R, caused by a G→A transition, was detected in exon 14 of the pro-VWF gene sequence. This mutation was not found on 200 chromosomes of normal individuals. The propositus was homozygous for the mutation and for an extended intragenic haplotype, composed of eight polymorphic markers. Further family members were heterozygous for the mutation and were phenotypically normal or only mildly affected, in accordance with the recessive pattern of inheritance for VWD type IIC. The mutation could influence one of the presumed active centers for the suspected multimerizing enzymatic activity of pro-VWF localized in the D1 and D2 domain, which corresponds to exon 5 and exon 14 of the VWF gene.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Armitage H, Rizza CR (1979) Two populations of factor VIII-related antigen in a family with von Willebrand's disease. Br J Haematol 41:279–289Google Scholar
  2. Batlle J, Lopez Fernandez MF, Lasierra J, Fernandez Villamor A, Lopez Berges C, Lopez Borrasca A, Ruggeri ZM, Zimmerman TS (1986) Von Willebrand disease type IIC with different abnormalities of von Willebrand factor in the same sibship. Am J Hematol 21: 177–188Google Scholar
  3. Bird AP (1980) DNA methylation and the frequency of CpG in animal DNA. Nucleic Acids Res 8: 1499–1504Google Scholar
  4. Bowen DJ, Webb CE, Peake IR, Bloom AL (1991) AatII polymorphism in von Willebrand factor gene at codon 471. Nucleic Acids Res 19:3159Google Scholar
  5. Brown JE, Bosak JO (1986) An ELISA test for the binding of von Willebrand antigen to collagen. Thromb Res 43:303–311Google Scholar
  6. Budowle B, Chakraborty R, Giusti AM, Eisenberg AJ, Allen RC (1991) Analysis of the VNTR locus DIS80 by the PCR followed by high resolution PAGE. Am J Hum Genet 48:137–144Google Scholar
  7. Bulleid NJ, Freedman RB (1988) Defective cotranslational formation of disulphide bonds in protein disulphide-isomerase-deficient microsomes. Nature 335:649–651Google Scholar
  8. Donner M, Holmberg L, Kristoffersson AC, Nilsson IM (1991) An HphI-polymorphism in exon 28 of the von Willebrand factor gene, and its frequency among patients with various forms of von Willebrand's disease. Br J Haematol 78:403–407Google Scholar
  9. Edman JC, Ellis L, Blacher RW, Roth RA, Rutter WJ (1985) Sequence of protein disulphide isomerase and implications of its relationship to thioredoxin. Nature 317:267–270Google Scholar
  10. Fowler WE, Fretto LJ, Hamilton KK, Erickson HP, McKee PA (1985) Substructure of human von Willebrand factor. J Clin Invest 76: 1491–1500Google Scholar
  11. Gaucher C, Diéval J, Mazurier C (1994) Characterization of von Willebrand factor gene defects in two unrelated patients with type IIC von Willebrand disease. Blood 84:1024–1030Google Scholar
  12. Ginsburg D, Sadler JE (1993) Von Willebrand disease: a database of point mutations, insertions, and deletions. For the Consortium on von Willebrand Factor Mutations and Polymorphisms, and the Subcommittee on von Willebrand Factor of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Thromb Haemost 69:177–184Google Scholar
  13. Holmberg L, Dent JA, Schneppenheim R, Budde U, Ware J, Ruggeri ZM (1993) Von Willebrand factor mutation enhancing interaction with platelets in patients with normal multimeric structure. J Clin Invest 91:2169–2177Google Scholar
  14. Kunkel GR, Graham JB, Fowlkes DM, Lord ST (1990) RsaI polymorphism in von Willebrand factor (VWF) at codon 789. Nucleic Acids Res 18:4961Google Scholar
  15. Kunkel GR, Graham JB, Fowlkes DM, Lord ST (1991) AccI polymorphism in von Willebrand factor (F8VWF) at codon 516. Nucleic Acids Res 19:1729Google Scholar
  16. Ledford MR, Rabinowitz I, Sadler JE, Kent JW, Civantos F (1993) New variant of von Willebrand disease type II with markedly increased levels of von Willebrand factor antigen and dominant mode of inheritance: von Willebrand disease type IIC Miami. Blood 82: 169–175Google Scholar
  17. Lowe T, Sharefkin J, Yang SQ, Dieffenbach CW (1990) A computer program for selection of oligonucleotide primers for polymerase chain reactions. Nucleic Acids Res 18: 1757–1761Google Scholar
  18. Macfarlane DE, Stibbe J, Kirby EP, Zucker MB, Grant RA, McPherson J (1975) Letter: a method for assaying von Willebrand factor (ristocetin cofactor). Thromb Diath Haemorrh 34: 306–308PubMedGoogle Scholar
  19. Mancuso DJ, Tuley EA, Westfield LA, Worrall NK, Shelton Inloes BB, Sorace JM, Alevy YG, Sadler JE (1989) Structure of the gene for human von Willebrand factor. J Biol Chem 264: 19514–19527Google Scholar
  20. Mancuso DJ, Tuley EA, Westfield LA, Lester Mancuso TL, Le Beau MM, Sorace JM, Sadler JE (1991) Human von Willebrand factor gene and pseudogene: structural analysis and differentiation by polymerase chain reaction. Biochemistry 30: 253–269Google Scholar
  21. Maniatis T, Fritsch EF, Sambrook J (1982) Molecular cloning: a laboratory manual, Cold Spring Harbor Laboratory Cold Spring Harbor, NYGoogle Scholar
  22. Mannucci PM, Lombardi R, Pareti FI, Solinas S, Mazzucconi MG, Mariani G (1983) A variant of von Willebrand's disease characterized by recessive inheritance and missing triplet structure of von Willebrand factor multimers. Blood 62: 1000–1005Google Scholar
  23. Mayadas TN, Wagner DD (1989) In vitro multimerization of von Willebrand factor is triggered by low pH. Importance of the propolypeptide and free sulfhydryls. J Biol Chem 264: 13497–13503Google Scholar
  24. Mayadas TN, Wagner DD (1992) Vicinal cysteines in the prosequence play a role in von Willebrand factor multimer assembly. Proc Natl Acad Sci USA 89:3531–3535Google Scholar
  25. Mazurier C, Parquet Gernez A, Goudemand M (1977) Enzyme-linked immunoabsorbent assay of factor VIII-related antigen. Interest in study of von Willebrand's disease. Pathol Biol (Paris) 25:18–24Google Scholar
  26. Mazurier C, Mannucci PM, Parquet Gernez A, Goudemand M, Meyer D (1986) Investigation of a case of subtype IIC von Willebrand disease: characterization of the variability of this subtype. Am J Hemalol 22:301–311Google Scholar
  27. Mercier B, Gaucher C, Mazurier C (1990) An MspI polymorphism in the von Willebrand factor gene. Nucleic Acids Res 18:7467Google Scholar
  28. Orita M, Iwahana H, Kanazawa H, Hayashi K, Sekiya T (1989) Detection of polymorphisms of human DNA by gel electrophoresis as single-strand conformation polymorphisms. Proc Natl Acad Sci USA 86:2766–2770PubMedGoogle Scholar
  29. Peake IR, Bowen D, Bignell P, Liddell MB, Sadler JE, Standen G, Bloom AL (1990) Family studies and prenatal diagnosis in severe von Willebrand disease by polymerase chain reaction amplification of a variable number tandem repeat region of the von Willebrand factor gene. Blood 76:555–561PubMedGoogle Scholar
  30. Ploos van Amstel HK, Reitsma PH (1990) Tetranucleotide repeat polymorphism in the VWF gene. Nucleic Acids Res 18:4957Google Scholar
  31. Raines G, Aumann H, Sykes S, Street A (1990) Multimeric analysis of von Willebrand factor by molecular sieving electrophoresis in sodium dodecyl sulphate agarose gel. Thromb Res 60: 201–212Google Scholar
  32. Ruggeri ZM (1987) Classification of von Willebrand disease. In: Verstraete M, Vermylen J, Lijnen R, Arnout J (eds) Thrombosis and haemostasis. Leuven University Press, Leuven pp 419–445Google Scholar
  33. Ruggeri ZM, Zimmerman TS (1981) The complex multimeric composition of factor VIII/von Willebrand factor. Blood 57: 1140–1143PubMedGoogle Scholar
  34. Ruggeri ZM, Nilsson IM, Lombardi R, Holmberg L, Zimmerman TS (1982) Aberrant multimeric structure of von Willebrand factor in a new variant of von Willebrand's disease (type IIC). J Clin Invest 70: 1124–1127Google Scholar
  35. Sadler JE (1994) A revised classification of von Willebrand disease. Thromb Haemost 71:520–525PubMedGoogle Scholar
  36. Saiki RK, Gelfand DH, Stoffel S, Scharf SJ, Higuchi R, Horn GT, Mullis KB, Erlich HA (1988) Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science 239:487–491PubMedGoogle Scholar
  37. Takahashi Y, Kalafatis M, Girma JP, Meyer D (1988) Abnormality of the N-terminal portion of von Willebrand factor in type IIA and IIC von Willebrand disease. Thromb Haemost 60:498–505Google Scholar
  38. Thomas KB, Sutor AH, Zieger B, Jessat U, Budde U, Grohmann A, Choong SC, Tune EP (1994) Von Willebrand factor — collagen binding activity and ristocetin cofactor activity. A comparison of methods able to differentiate von Willebrand disease type I and II. Hämostaseologie 14: 133–139Google Scholar
  39. Verweij CL, Hart M, Pannekoek H (1987) Expression of variant von Willebrand factor (VWF) cDNA in heterologous cells: requirement of the pro-polypeptide in VWF multimer formation. EMBO J 6:2885–2890Google Scholar
  40. Wagner DD (1990) Cell biology of von Willebrand factor. Annu Rev Cell Biol 6:217–246Google Scholar
  41. Wise RJ, Pittman DD, Handin RI, Kaufman RJ, Orkin SH (1988) The propeptide of von Willebrand factor independently mediates the assembly of von Willebrand multimers. Cell 52:229–236Google Scholar
  42. Zimmerman TS, Dent JA, Ruggerie ZM, Nannini LH (1986) Sub-unit composition of plasma von Willebrand factor. Cleavage is present in normal individuals, increased in IIA and IIB von Willebrand disease, but minimal in variants with aberrant structure of individual oligomers (type IIC, IID and IIE). J Clin Invest 77:947–951Google Scholar

Copyright information

© Springer-Verlag 1995

Authors and Affiliations

  • Reinhard Schneppenheim
    • 1
  • Kathy B. Thomas
    • 2
  • Sonja Krey
    • 1
  • Ulrich Budde
    • 3
  • Ursula Jessat
    • 2
  • Anton H. Sutor
    • 2
  • Barbara Zieger
    • 4
  1. 1.Universitäts-Kinderklinik KielKielGermany
  2. 2.Universitäts-Kinderklinik FreiburgFreiburgGermany
  3. 3.Allg. Krankenhaus HarburgHamburgGermany
  4. 4.Scripps Clinic and Research FoundationLa JollaUSA

Personalised recommendations