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. 1987 May;79(5):1459–1465. doi: 10.1172/JCI112974

Gene deletions correlate with the development of alloantibodies in von Willebrand disease.

B B Shelton-Inloes, F F Chehab, P M Mannucci, A B Federici, J E Sadler
PMCID: PMC424419  PMID: 3033024

Abstract

Among all patients with von Willebrand disease (vWD), alloantibodies to von Willebrand factor (vWF) have been described only in severe vWD (type III). The relationship between the development of alloantibodies and the nature of the genetic lesion in vWD is not known. In hemophilia B, large deletions within the factor IX gene appear to correlate with the occurrence of alloantibodies, whereas in hemophilia A no such correlation is apparent. We have studied 19 patients with severe recessive vWD (type III) and 19 with autosomal dominant vWD (type I) by Southern blotting with probes encompassing the full 9 kilobases (kb) of the vWF cDNA. Two apparently unrelated patients were shown to have large deletions within the vWF gene. Both patients had severe vWD (type III) and were the only patients among those studied that had inhibitory alloantibodies to vWF. The extent of deletion was similar in both patients, corresponding to at least the 3'-7.4 kb of the vWF cDNA. The deletion in each patient was estimated to exceed 110 kb. In addition, the localization of the vWF gene to chromosome 12 was confirmed, and a homologous sequence on chromosome 22 was identified.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Antonarakis S. E., Waber P. G., Kittur S. D., Patel A. S., Kazazian H. H., Jr, Mellis M. A., Counts R. B., Stamatoyannopoulos G., Bowie E. J., Fass D. N. Hemophilia A. Detection of molecular defects and of carriers by DNA analysis. N Engl J Med. 1985 Oct 3;313(14):842–848. doi: 10.1056/NEJM198510033131402. [DOI] [PubMed] [Google Scholar]
  2. Bernardi F., del Senno L., Barbieri R., Buzzoni D., Gambari R., Marchetti G., Conconi F., Panicucci F., Positano M., Pitruzzello S. Gene deletion in an Italian haemophilia B subject. J Med Genet. 1985 Aug;22(4):305–307. doi: 10.1136/jmg.22.4.305. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Campbell R. D., Bentley D. R., Morley B. J. The factor B and C2 genes. Philos Trans R Soc Lond B Biol Sci. 1984 Sep 6;306(1129):367–378. doi: 10.1098/rstb.1984.0097. [DOI] [PubMed] [Google Scholar]
  4. Chomczynski P., Qasba P. K. Alkaline transfer of DNA to plastic membrane. Biochem Biophys Res Commun. 1984 Jul 18;122(1):340–344. doi: 10.1016/0006-291x(84)90480-7. [DOI] [PubMed] [Google Scholar]
  5. Fay P. J., Kawai Y., Wagner D. D., Ginsburg D., Bonthron D., Ohlsson-Wilhelm B. M., Chavin S. I., Abraham G. N., Handin R. I., Orkin S. H. Propolypeptide of von Willebrand factor circulates in blood and is identical to von Willebrand antigen II. Science. 1986 May 23;232(4753):995–998. doi: 10.1126/science.3486471. [DOI] [PubMed] [Google Scholar]
  6. Feinberg A. P., Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem. 1983 Jul 1;132(1):6–13. doi: 10.1016/0003-2697(83)90418-9. [DOI] [PubMed] [Google Scholar]
  7. Fujimura Y., Titani K., Holland L. Z., Russell S. R., Roberts J. R., Elder J. H., Ruggeri Z. M., Zimmerman T. S. von Willebrand factor. A reduced and alkylated 52/48-kDa fragment beginning at amino acid residue 449 contains the domain interacting with platelet glycoprotein Ib. J Biol Chem. 1986 Jan 5;261(1):381–385. [PubMed] [Google Scholar]
  8. Giannelli F., Brownlee G. G. Cause of the 'inhibitor' phenotype in the haemophilias. Nature. 1986 Mar 13;320(6058):196–196. doi: 10.1038/320196a0. [DOI] [PubMed] [Google Scholar]
  9. Giannelli F., Choo K. H., Rees D. J., Boyd Y., Rizza C. R., Brownlee G. G. Gene deletions in patients with haemophilia B and anti-factor IX antibodies. Nature. 1983 May 12;303(5913):181–182. doi: 10.1038/303181a0. [DOI] [PubMed] [Google Scholar]
  10. Ginsburg D., Handin R. I., Bonthron D. T., Donlon T. A., Bruns G. A., Latt S. A., Orkin S. H. Human von Willebrand factor (vWF): isolation of complementary DNA (cDNA) clones and chromosomal localization. Science. 1985 Jun 21;228(4706):1401–1406. doi: 10.1126/science.3874428. [DOI] [PubMed] [Google Scholar]
  11. Gitschier J., Wood W. I., Tuddenham E. G., Shuman M. A., Goralka T. M., Chen E. Y., Lawn R. M. Detection and sequence of mutations in the factor VIII gene of haemophiliacs. 1985 May 30-Jun 5Nature. 315(6018):427–430. doi: 10.1038/315427a0. [DOI] [PubMed] [Google Scholar]
  12. Grunebaum L., Cazenave J. P., Camerino G., Kloepfer C., Mandel J. L., Tolstoshev P., Jaye M., De la Salle H., Lecocq J. P. Carrier detection of Hemophilia B by using a restriction site polymorphism associated with the coagulation Factor IX gene. J Clin Invest. 1984 May;73(5):1491–1495. doi: 10.1172/JCI111354. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Holmberg L., Nilsson I. M. Von Willebrand disease. Clin Haematol. 1985 Jun;14(2):461–488. [PubMed] [Google Scholar]
  14. Hoyer L. W. The factor VIII complex: structure and function. Blood. 1981 Jul;58(1):1–13. [PubMed] [Google Scholar]
  15. Jaffe E. A., Hoyer L. W., Nachman R. L. Synthesis of antihemophilic factor antigen by cultured human endothelial cells. J Clin Invest. 1973 Nov;52(11):2757–2764. doi: 10.1172/JCI107471. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Jaffe E. A., Hoyer L. W., Nachman R. L. Synthesis of von Willebrand factor by cultured human endothelial cells. Proc Natl Acad Sci U S A. 1974 May;71(5):1906–1909. doi: 10.1073/pnas.71.5.1906. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Kapuściński J., Skoczylas B. Simple and rapid fluorimetric method for DNA microassay. Anal Biochem. 1977 Nov;83(1):252–257. doi: 10.1016/0003-2697(77)90533-4. [DOI] [PubMed] [Google Scholar]
  18. Kapuściński J., Yanagi K. Selective staining by 4', 6-diamidine-2-phenylindole of nanogram quantities of DNA in the presence of RNA on gels. Nucleic Acids Res. 1979 Aug 10;6(11):3535–3542. doi: 10.1093/nar/6.11.3535. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Lebo R. V., Gorin F., Fletterick R. J., Kao F. T., Cheung M. C., Bruce B. D., Kan Y. W. High-resolution chromosome sorting and DNA spot-blot analysis assign McArdle's syndrome to chromosome 11. Science. 1984 Jul 6;225(4657):57–59. doi: 10.1126/science.6587566. [DOI] [PubMed] [Google Scholar]
  20. Lynch D. C., Zimmerman T. S., Collins C. J., Brown M., Morin M. J., Ling E. H., Livingston D. M. Molecular cloning of cDNA for human von Willebrand factor: authentication by a new method. Cell. 1985 May;41(1):49–56. doi: 10.1016/0092-8674(85)90060-1. [DOI] [PubMed] [Google Scholar]
  21. Mannucci P. M., Mari D. Antibodies to factor VIII-von Willebrand factor in congenital and acquired von Willebrand's disease. Prog Clin Biol Res. 1984;150:109–122. [PubMed] [Google Scholar]
  22. Mannucci P. M., Meyer D., Ruggeri Z. M., Koutts J., Ciavarella N., Lavergne J. M. Precipitating antibodies in von Willebrand's disease. Nature. 1976 Jul 8;262(5564):141–142. doi: 10.1038/262141a0. [DOI] [PubMed] [Google Scholar]
  23. Nachman R., Levine R., Jaffe E. A. Synthesis of factor VIII antigen by cultured guinea pig megakaryocytes. J Clin Invest. 1977 Oct;60(4):914–921. doi: 10.1172/JCI108846. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Peake I. R., Furlong B. L., Bloom A. L. Carrier detection by direct gene analysis in a family with haemophilia B (factor IX deficiency). Lancet. 1984 Feb 4;1(8371):242–243. doi: 10.1016/s0140-6736(84)90123-5. [DOI] [PubMed] [Google Scholar]
  25. Ruggeri Z. M., Ciavarella N., Mannucci P. M., Molinari A., Dammacco F., Lavergne J. M., Meyer D. Familial incidence of precipitating antibodies in von Willebrand's disease: a study of four cases. J Lab Clin Med. 1979 Jul;94(1):60–75. [PubMed] [Google Scholar]
  26. Sadler J. E., Shelton-Inloes B. B., Sorace J. M., Harlan J. M., Titani K., Davie E. W. Cloning and characterization of two cDNAs coding for human von Willebrand factor. Proc Natl Acad Sci U S A. 1985 Oct;82(19):6394–6398. doi: 10.1073/pnas.82.19.6394. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Shapiro S. S. Antibodies to blood coagulation factors. Clin Haematol. 1979 Feb;8(1):207–214. [PubMed] [Google Scholar]
  28. Shelton-Inloes B. B., Titani K., Sadler J. E. cDNA sequences for human von Willebrand factor reveal five types of repeated domains and five possible protein sequence polymorphisms. Biochemistry. 1986 Jun 3;25(11):3164–3171. doi: 10.1021/bi00359a014. [DOI] [PubMed] [Google Scholar]
  29. Titani K., Kumar S., Takio K., Ericsson L. H., Wade R. D., Ashida K., Walsh K. A., Chopek M. W., Sadler J. E., Fujikawa K. Amino acid sequence of human von Willebrand factor. Biochemistry. 1986 Jun 3;25(11):3171–3184. doi: 10.1021/bi00359a015. [DOI] [PubMed] [Google Scholar]
  30. 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]
  31. Verweij C. L., Diergaarde P. J., Hart M., Pannekoek H. Full-length von Willebrand factor (vWF) cDNA encodes a highly repetitive protein considerably larger than the mature vWF subunit. EMBO J. 1986 Aug;5(8):1839–1847. doi: 10.1002/j.1460-2075.1986.tb04435.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Verweij C. L., de Vries C. J., Distel B., van Zonneveld A. J., van Kessel A. G., van Mourik J. A., Pannekoek H. Construction of cDNA coding for human von Willebrand factor using antibody probes for colony-screening and mapping of the chromosomal gene. Nucleic Acids Res. 1985 Jul 11;13(13):4699–4717. doi: 10.1093/nar/13.13.4699. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Yanisch-Perron C., Vieira J., Messing J. Improved M13 phage cloning vectors and host strains: nucleotide sequences of the M13mp18 and pUC19 vectors. Gene. 1985;33(1):103–119. doi: 10.1016/0378-1119(85)90120-9. [DOI] [PubMed] [Google Scholar]

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