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. 1991 Jul 15;88(14):6377–6381. doi: 10.1073/pnas.88.14.6377

Expression of von Willebrand factor "Normandy": an autosomal mutation that mimics hemophilia A.

E A Tuley 1, C Gaucher 1, S Jorieux 1, N K Worrall 1, J E Sadler 1, C Mazurier 1
PMCID: PMC52086  PMID: 1906179

Abstract

von Willebrand disease Normandy (vWD Normandy) is a recently described phenotype in which a mutant von Willebrand factor (vWF) appears structurally and functionally normal except that it does not bind to blood coagulation factor VIII. This interaction is required for normal survival of factor VIII in the circulation; consequently, vWD Normandy can present as apparent hemophilia A but with autosomal recessive rather than X chromosome-linked inheritance. A vWF missense mutation, Thr28----Met, was identified in the propositus in or near the factor VIII binding site. The corresponding mutant recombinant vWF(T28M) formed normal multimers and had normal ristocetin cofactor activity. However, vWF(T28M) exhibited the same defect in factor VIII binding as natural vWF Normandy, confirming that this mutation causes the vWD Normandy phenotype. The distinction between hemophilia A and vWD Normandy is clinically important and should be considered in families affected by apparent mild hemophilia A that fail to show strict X chromosome-linked inheritance and, particularly, in potential female carriers with low factor VIII levels attributed to extreme lyonization.

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Selected References

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  1. Adams G. A., Rose J. K. Incorporation of a charged amino acid into the membrane-spanning domain blocks cell surface transport but not membrane anchoring of a viral glycoprotein. Mol Cell Biol. 1985 Jun;5(6):1442–1448. doi: 10.1128/mcb.5.6.1442. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bahou W. F., Ginsburg D., Sikkink R., Litwiller R., Fass D. N. A monoclonal antibody to von Willebrand factor (vWF) inhibits factor VIII binding. Localization of its antigenic determinant to a nonadecapeptide at the amino terminus of the mature vWF polypeptide. J Clin Invest. 1989 Jul;84(1):56–61. doi: 10.1172/JCI114169. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Burke R. L., Pachl C., Quiroga M., Rosenberg S., Haigwood N., Nordfang O., Ezban M. The functional domains of coagulation factor VIII:C. J Biol Chem. 1986 Sep 25;261(27):12574–12578. [PubMed] [Google Scholar]
  4. Chopek M. W., Girma J. P., Fujikawa K., Davie E. W., Titani K. Human von Willebrand factor: a multivalent protein composed of identical subunits. Biochemistry. 1986 Jun 3;25(11):3146–3155. doi: 10.1021/bi00359a012. [DOI] [PubMed] [Google Scholar]
  5. DOUGLAS A. S. Antihemophilic globulin assay following plasma infusions in hemophilia. J Lab Clin Med. 1958 Jun;51(6):850–859. [PubMed] [Google Scholar]
  6. Foster P. A., Fulcher C. A., Marti T., Titani K., Zimmerman T. S. A major factor VIII binding domain resides within the amino-terminal 272 amino acid residues of von Willebrand factor. J Biol Chem. 1987 Jun 25;262(18):8443–8446. [PubMed] [Google Scholar]
  7. Gaucher C., Jorieux S., Mercier B., Oufkir D., Mazurier C. The "Normandy" variant of von Willebrand disease: characterization of a point mutation in the von Willebrand factor gene. Blood. 1991 May 1;77(9):1937–1941. [PubMed] [Google Scholar]
  8. Howard M. A., Firkin B. G. Ristocetin--a new tool in the investigation of platelet aggregation. Thromb Diath Haemorrh. 1971 Oct 31;26(2):362–369. [PubMed] [Google Scholar]
  9. Kingston R. E., Kaufman R. J., Sharp P. A. Regulation of transcription of the adenovirus EII promoter by EIa gene products: absence of sequence specificity. Mol Cell Biol. 1984 Oct;4(10):1970–1977. doi: 10.1128/mcb.4.10.1970. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
  11. Mancuso D. J., Tuley E. A., Westfield L. A., Worrall N. K., Shelton-Inloes B. B., Sorace J. M., Alevy Y. G., Sadler J. E. Structure of the gene for human von Willebrand factor. J Biol Chem. 1989 Nov 25;264(33):19514–19527. [PubMed] [Google Scholar]
  12. Mazurier C., Dieval J., Jorieux S., Delobel J., Goudemand M. A new von Willebrand factor (vWF) defect in a patient with factor VIII (FVIII) deficiency but with normal levels and multimeric patterns of both plasma and platelet vWF. Characterization of abnormal vWF/FVIII interaction. Blood. 1990 Jan 1;75(1):20–26. [PubMed] [Google Scholar]
  13. Mazurier C., Gaucher C., Jorieux S., Parquet-Gernez A., Goudemand M. Evidence for a von Willebrand factor defect in factor VIII binding in three members of a family previously misdiagnosed mild haemophilia A and haemophilia A carriers: consequences for therapy and genetic counselling. Br J Haematol. 1990 Nov;76(3):372–379. doi: 10.1111/j.1365-2141.1990.tb06371.x. [DOI] [PubMed] [Google Scholar]
  14. Nishino M., Girma J. P., Rothschild C., Fressinaud E., Meyer D. New variant of von Willebrand disease with defective binding to factor VIII. Blood. 1989 Oct;74(5):1591–1599. [PubMed] [Google Scholar]
  15. Over J., Sixma J. J., Bruïne M. H., Trieschnigg M. C., Vlooswijk R. A., Beeser-Visser N. H., Bouma B. N. Survival of 125iodine-labeled Factor VIII in normals and patients with classic hemophilia. Observations on the heterogeneity of human Factor VIII. J Clin Invest. 1978 Aug;62(2):223–234. doi: 10.1172/JCI109120. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Piétu G., Ribba A. S., Meulien P., Meyer D. Localization within the 106 N-terminal amino acids of von Willebrand factor (vWF) of the epitope corresponding to a monoclonal antibody which inhibits vWF binding to factor VIII. Biochem Biophys Res Commun. 1989 Aug 30;163(1):618–626. doi: 10.1016/0006-291x(89)92182-7. [DOI] [PubMed] [Google Scholar]
  17. Raines G., Aumann H., Sykes S., Street A. Multimeric analysis of von Willebrand factor by molecular sieving electrophoresis in sodium dodecyl sulphate agarose gel. Thromb Res. 1990 Nov 1;60(3):201–212. doi: 10.1016/0049-3848(90)90181-b. [DOI] [PubMed] [Google Scholar]
  18. Rose J. K., Bergmann J. E. Expression from cloned cDNA of cell-surface secreted forms of the glycoprotein of vesicular stomatitis virus in eucaryotic cells. Cell. 1982 Oct;30(3):753–762. doi: 10.1016/0092-8674(82)90280-x. [DOI] [PubMed] [Google Scholar]
  19. Saiki R. K., Gelfand D. H., Stoffel S., Scharf S. J., Higuchi R., Horn G. T., Mullis K. B., Erlich H. A. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science. 1988 Jan 29;239(4839):487–491. doi: 10.1126/science.2448875. [DOI] [PubMed] [Google Scholar]
  20. Sanger F., Nicklen S., Coulson A. R. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. doi: 10.1073/pnas.74.12.5463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Takahashi Y., Kalafatis M., Girma J. P., Sewerin K., Andersson L. O., Meyer D. Localization of a factor VIII binding domain on a 34 kilodalton fragment of the N-terminal portion of von Willebrand factor. Blood. 1987 Nov;70(5):1679–1682. [PubMed] [Google Scholar]
  22. Tuddenham E. G., Lane R. S., Rotblat F., Johnson A. J., Snape T. J., Middleton S., Kernoff P. B. Response to infusions of polyelectrolyte fractionated human factor VIII concentrate in human haemophilia A and von Willebrand's disease. Br J Haematol. 1982 Oct;52(2):259–267. doi: 10.1111/j.1365-2141.1982.tb03888.x. [DOI] [PubMed] [Google Scholar]
  23. Urlaub G., Mitchell P. J., Kas E., Chasin L. A., Funanage V. L., Myoda T. T., Hamlin J. Effect of gamma rays at the dihydrofolate reductase locus: deletions and inversions. Somat Cell Mol Genet. 1986 Nov;12(6):555–566. doi: 10.1007/BF01671941. [DOI] [PubMed] [Google Scholar]
  24. Wagner D. D. Cell biology of von Willebrand factor. Annu Rev Cell Biol. 1990;6:217–246. doi: 10.1146/annurev.cb.06.110190.001245. [DOI] [PubMed] [Google Scholar]
  25. Wagner D. D., Saffaripour S., Bonfanti R., Sadler J. E., Cramer E. M., Chapman B., Mayadas T. N. Induction of specific storage organelles by von Willebrand factor propolypeptide. Cell. 1991 Jan 25;64(2):403–413. doi: 10.1016/0092-8674(91)90648-i. [DOI] [PubMed] [Google Scholar]

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