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Thromb Haemost 1999; 82(03): 1061-1064
DOI: 10.1055/s-0037-1614329
DOI: 10.1055/s-0037-1614329
Letters to the Editor
A Common Splice Site Mutation Is Shared by Two Families with Different Type 2N von Willebrand Disease Mutations
Authors
Weitere Informationen
Publikationsverlauf
Received
31. Dezember 1998
Accepted after revision
14. April 1999
Publikationsdatum:
09. Dezember 2017 (online)
Summary
Using an ELISA-based method to detect type 2N von Willebrand disease (VWD), we found two individuals with absent FVIII binding. Direct sequencing of the FVIII binding region of the von Willebrand factor (VWF) gene showed that one individual had an R854Q substitution whilst the other had a T791M substitution. The very low FVIII binding and the VWF:Ag levels in both individuals suggested a second defect on the other VWF allele. Conformation sensitive gel electrophoresis of polymerase chain reaction amplified DNA was used to detect an additional change in the VWF gene of each patient. Direct sequencing confirmed a previously unreported G to A transition in the donor splice site in intron 25 of both individuals which should result in a null allele. This was confirmed by mRNA analysis. These two individuals therefore have compound heterozygous VWD in which the only expressed allele has a type 2N mutation. In our population, such compound heterozygosity appears to be a significant cause of type 2N VWD.
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References
- 1 Sakariassen KS, Nievelstein PFEM, Coller BS, Sixma JJ. The role of platelet membrane glycoprotein Ib and IIb-IIIa in platelet adherence to human artery subendothelium. Br J Haematol 1986; 63: 681-91.
- 2 Weiss HJ, Sussman II, Hoyer LW. Stabilisation of the FVIII in plasma by the von Willebrand factor. J Clin Invest 1977; 60: 309-404.
- 3 Ginsburg D, Handin RI, Bonthron DT, Donlon TA, Bruns GAP, Latt SA, Orkin SH. Human von Willebrand factor (VWF): Isolation of complementary DNA (cDNA) clones and chromosomal localisation. Science 1985; 228: 1401-6.
- 4 Bonthron DT, Handin RI, Kaufman RJ, Wasley LC, Orr EC, Mitsock LM, Ewenstein B, Loscalzo J, Ginsburg D, Orkin SH. Structure of pre-pro-von Willebrand factor and its expression in heterologous cells. Nature 1986; 324: 270-3.
- 5 Verweij CL, Diergaarde PJ, 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; 5: 1839-1847.
- 6 Rodeghiero F, Castaman G, Dini E. Epidemiological investigation of the prevalence of VWD. Blood 1987; 69: 454-9.
- 7 Sadler JE, Matsushita T, Dong Z, Tuley EA, Westfield LA. Molecular mechanism and classification of von Willebrand disease. Thromb Haemost 1995; 74: 161-6
- 8 Mazurier C. von Willebrand disease masquerading as Haemophilia A. Thromb Haemost 1992; 67: 391-6.
- 9 Foster PA, Fulcher CA, Marti T, Titani K, Zimmerman TS. A major FVIII binding domain resides within the amino-terminal 272 amino-acid residues of von Willebrand factor. J Biol Chem 1987; 262: 8443-6.
- 10 Takahashi Y, Kalafatis M, Girma J-P, Sewein K, Andersson L-O, Meyer D. Localisation of a FVIII binding domain on a 34 kilodalton fragment of the N-terminal portion of von Willebrand factor. Blood 1987; 70: 1679-82.
- 11 Kroner PA, Fahs SA, Vokac EA, Freidman KD, Montgomery RR. Novel missense mutations in von Willebrand factor (VWF) associated with defective VWF/FVIII interaction in a patient with type 1 von Willebrand disease. Blood 1991; 78 (Suppl. 01) 1278a (Abstract).
- 12 Scheppenheim R, Budde U, Krey S, Drewke E, Lechler E, Oldenberg J, Schwaab R. Compound heterozygosity for AC and mutations in the factor VIII binding domain of von Willebrand factor and the description of a novel mutation (E24K) correlated with a more severe form of von Willebrand disease type Normandy. Thromb Haemost 1995; 73: 1169 (Abstract).
- 13 Tuley EA, Gaucher C, Jorieux S, Worrall NK, Sadler JE, Mazurier C. Expression of von Willebrand factor “Normandy”: An autosomal mutation that mimics haemophilia A. Proc Nat Acad Sci USA 1991; 88: 6377-81.
- 14 Gaucher C, Jorieux S, Mercier B, Oufkir D, Mazurier C. The “Normandy” variant of von Willebrand disease: Characterisation of a point mutation in the von Willebrand factor gene. Blood 1991; 77: 1937-41.
- 15 Cacheris PM, Nichols WC, Ginsburg D. Molecular characterisation of a unique von Willebrand variant. A novel mutation affecting von Willebrand factor/factor VIII interaction. J Biol Chem 1991; 88: 13499-502.
- 16 Bowen DJ, Standen GR, Mazurier C, Gaucher C, Cumming A, Keeney S, Bidwell J. Type 2N Von Willebrand disease: Rapid genetic diagnosis of G2811A (R854Q), C2696T (R816W), T2701A (H817Q), and G2823T (C858F), – Detection of a novel candidate type 2N mutation: C2810T (R854W). Thromb Haemost 1998; 80: 32-6.
- 17 Gu J, Jorieux S, Lavergne JM, Ruan C, Mazurier C, Meyer D. Patient with type 2N von Willebrand disease is heterozygous for a new mutation: Gly22Glu. Demonstration of a defective expression of the second allele by the use of monoclonal antibodies. Blood 1997; 89: 3263-9.
- 18 Jorieux S, Gaucher C, Goudemand J, Mazurier C. A novel mutation in the D3 domain of VWF abolishes the FVIII binding and affects the multimerisation. Haemophilia 1996; 2 (Suppl. 01) 329 (Abstract).
- 19 Ginsburg D, Sadler JE. Von Willebrand factor database. 1997 http://mmg2.im.med.umich.edu/vWF/
- 20 Nesbitt IM, Goodeve AC, Guilliatt AM, Makris M, Preston FE, Peake IR. Characterisation of type 2N von Willebrand disease using phenotypic and molecular techniques. Thromb Haemost 1996; 75: 959-64.
- 21 Chomczynski P, Sacchi N. Single step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 1987; 162: 156-9.
- 22 Giddings JC, Peake IR. Principles of immunoassays of haemostatic components. In: Haemostasis and Thrombosis. Bloom AL, Thomas DP. eds. Churchill Livingstone; Edinburgh: 1981: 824-31.
- 23 Saiki RK, Gelfand DH, Stoffer S, Scharf SJ, Higuchi R, Horn GT, Mullis KB, Erlich HA. Primer directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science 1988; 239: 487-91.
- 24 Zhang ZP, Blombäck M, Egberg N, Falk G, Anvret M. Characterisation of the von Willebrand factor gene (VWF) in von Willebrand disease type III patients from 24 families of Swedish and Finnish origin. Genomics 1994; 21: 188-93.
- 25 Williams IJ, Abuzenadah A, Winship PR, Preston FE, Dolan G, Wright J, Peake IR, Goodeve AC. Precise carrier detection in families with haemophilia A: Use of conformation sensitive gel electrophoresis for mutation screening and polymorphism analysis. Thromb Haemost 1998; 79: 723-6.
- 26 Ploos van Amstel H, Reitsma PH. Tetranucleotide repeat polymorphism in the vWF gene. Nucl Acids Res 1990; 18: 4957.
- 27 Mancuso DJ, Tuley EA, Westfield LA, Worral NK, Shelton-Inloes BB, Sorace JM, Alevy YG, Sadler JE. Structure of the gene for human von Willebrand factor. J Biol Chem 1989; 264: 19514-27.
- 28 Mazurier C, Meyer D. Factor VIII binding assay of Von Willebrand factor and the diagnosis of type 2N Von Willebrand disease – results of an international survey. Thromb Haemost 1996; 76: 720-4.
- 29 Peerlinck K, Eikenboom JCJ, Ploos Van Amstel HK, Sangtawesin W, Arnout J, Reitsma PH, Vermylen J, Briet E. A patient with von Willebrand’s disease characterised by a compound heterozygosity for a substitution of Arg854 by Gln in the putative factor VIII binding domain of von Willebrand factor (vWF) on one allele and very low levels of mRNA from the second vWF allele. Br J Haematol 80: 358-63.
- 30 Eikenboom JCJ, Castaman G, Vos HL, Bertina RM, Rodeghiero F. Characterisation of the genetic defects in recessive type 1 and type 3 von Willebrand disease patients of Italian origin. Thromb Haemost 1998; 79: 709-17.
- 31 Laverne JM, Gu J, Jorieux S, RastegarLari G, Ruan C, Mazurier C, Meyer D. New mutations of von Willebrand factor Y271ter and G785E (Gly22Glu) in a compound heterozygous patient with type 2N von Willebrand disease. Thromb Haemost 1997; No SS 2666.
- 32 Meyer D, Fressinaud E, Gaucher C, Lavergne J-M, Hilbert L, Ribba A-S, Jorieux S, Mazurier C. the INSERM Network on Molecular Abnormalities. in von Willebrand Disease. Thromb Haemost 1997; 78: 451-456.
- 33 Homberg L, Karpman D, Isaksson C, Kristofferson AC, Lethagen S, Schneppenheim R. Ins405AsnPro mutation in the von Willebrand factor propeptide in recessive type 2A (IIC) von Willebrand’s disease. Thromb Haemost 1998; 79: 718-722.
- 34 Hinks JL, Winship PR, Makris M, Perston FE, Peake IR, Goodeve AC. A rapid method for haemophilia B mutation detection using conformation sensitive gel electrophoresis. Br J Haematol. 1999; 104: 915-918.
- 35 Gari M, Goodeve A, Wilson G, Winship P, Langabeer S, Linch D, Vandenberghe E, Peake I, Reilly J. c-kit proto-oncogene exon 8 in-frame deletion plus insertion mutations in acute myeloid leukaemia. In press.