Characterization of the Genetic Defects in Recessive Type 1 and Type 3 von Willebrand Disease Patients of Italian Origin

Summary

The genetic defects causing recessive type 1 and type 3 von Wille-brand disease (VWD) in eight families from the northern part of Italy have been investigated. Mutations were identified in 14 of the 16 disease-associated von Willebrand factor (VWF) genes. Only one mutation, a stop codon in exon 45, was previously reported. Several new mutations were identified: one cytosine insertion in exon 42, one guanine deletion in exon 28, one probably complete VWF gene deletion, one substitution in the 3’ splice site of intron 13, one possible gene conversion, and three candidate missense mutations. One missense mutation, the substitution of a cysteine in exon 42, was identified in all type 3 VWD patients that were previously characterized as a subgroup with significant increase of factor VIII procoagulant activity after desmopressin infusion. This paper demonstrates again that the molecular defects of quantitative VWD are diverse and located throughout the entire VWF gene.

• References

• 1 Rodeghiero F, Castaman G, Dini E. Epidemiological investigation of the prevalence of von Willebrand’s disease. Blood 1987; 69: 454-9.
• 2 Werner EJ, Broxson EH, Tucker EL, Giroux DS, Shults J, Abshire TC. Prevalence of von Willebrand disease in children: A multi-ethnic study. J Pediatr 1993; 123: 893-8.
• 3 Bloom AL. Von Willebrand factor: clinical features of inherited and acquired disorders. Mayo Clin Proc 1991; 66: 743-51.
• 4 Ginsburg D, Handin RI, Bonthron DT, Donlon TA, Bruns GA, Latt SA, Orkin SH. Human von Willebrand factor (vWF): isolation of complementary DNA (cDNA) clones and chromosomal localization. Science 1985; 228: 1401-6.
• 5 Verweij CL, de Vries CJ, Distel B, van Zonneveld AJ, van Kessel AG, Van Mourik JA, 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; 13: 4699-717.
• 6 Sadler JE. A revised classification of von Willebrand disease. Thromb Haemost 1994; 71: 520-5.
• 7 Ginsburg D, Sadler JE. Von Willebrand disease: A database of point mutations, insertions, and deletions. Thromb Haemost 1993; 69: 177-84.
• 8 Ginsburg D, Bowie EJW. Molecular genetics of von Willebrand disease. Blood 1992; 79: 2507-19.
• 9 Mazurier C. Von Willebrand disease masquerading as haemophilia A. Thromb Haemost 1992; 67: 391-6.
• 10 Mohri H, Fujimura Y, Shima M, Yoshioka A, Houghton RA, Ruggeri ZM, Zimmerman TS. Structure of the von Willebrand factor domain interacting with glycoprotein Ib. J Biol Chem 1988; 263: 17901-4.
• 11 Berndt MC, Ward CM, Booth WJ, Castaldi PA, Mazurov AV, Andrews RK. Identification of aspartic acid 514 through glutamic acid 542 as a glycoprotein Ib-IX complex receptor recognition sequence in von Willebrand factor. Mechanism of modulation of von Willebrand factor by ristocetin and botrocetin. Biochemistry 1992; 31: 11144-51.
• 12 Peake IR, Liddell MB, Moodie P, Standen G, Mancuso DJ, Tuley EA, Westfield LA, Sorace JM, Sadler JE, Verweij CL, Bloom AL. Severe type III von Willebrand’s disease caused by deletion of exon 42 of the von Willebrand factor gene: family studies that identify carriers of the condition and a compound heterozygous individual. Blood 1990; 75: 654-61.
• 13 Ngo KY, Glotz VT, Koziol JA, Lynch DC, Gitschier J, Ranieri P, Ciavarella N, Ruggeri ZM, Zimmerman TS. Homozygous and heterozygous deletions of the von Willebrand factor gene in patients and carriers of severe von Willebrand disease. Proc Natl Acad Sci USA 1988; 85: 2753-7.
• 14 Shelton-Inloes BB, Chehab FF, Mannucci PM, Federici AB, Sadler JE. Gene deletions correlate with the development of alloantibodies in von Willebrand disease. J Clin Invest 1987; 79: 1459-65.
• 15 Mancuso DJ, Tuley EA, Castillo R, De Bosch N, Mannucci PM, Sadler JE. Characterization of partial gene deletions in type III von Willebrand disease with alloantibody inhibitors. Thromb Haemost 1994; 72: 180-5.
• 16 Schneppenheim R, Krey S, Bergmann F, Bock D, Budde U, Lange M, Linde R, Mittler U, Meili E, Mertes G, Olek K, Plendl H, Simeoni E. Genetic heterogeneity of severe von Willebrand disease type III in the German population. Hum Genet 1994; 94: 640-52.
• 17 Zhang ZP, Falk G, Blombäck M, Egberg N, Anvret M. A single cytosine deletion in exon 18 of the von Willebrand factor gene is the most common mutation in Swedish vWD type III patients. Hum Mol Genet 1992; 1: 767-8.
• 18 Zhang ZP, Blombäck M, Egberg N, Falk G, Anvret M. Characterization 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.
• 19 Eikenboom JCJ, Ploos van Amstel HK, Reitsma PH, Briët E. Mutations in severe, type III von Willebrand’s disease in the Dutch population: Candidate missense and nonsense mutations associated with reduced levels of von Willebrand factor messenger RNA. Thromb Haemost 1992; 68: 448-54.
• 20 Zhang ZP, Falk G, Blombäck M, Egberg N, Anvret M. Identification of a new nonsense mutation in the von Willebrand factor gene in patients with von Willebrand disease type III. Hum Mol Genet 1992; 1: 61-2.
• 21 Bahnak BR, Lavergne JM, Rothschild C, Meyer D. A stop codon in a patient with severe type III von Willebrand disease [letter]. Blood 1991; 78: 1148-9.
• 22 Zhang ZP, Lindstedt M, Falk G, Blombäck M, Egberg N, Anvret M. Nonsense mutations of the von Willebrand factor gene in patients with von Willebrand disease type III and type I. Am J Hum Genet 1992; 51: 850-8.
• 23 Mertes G, Ludwig M, Finkelnburg B, Krawczak M, Schwaab R, Brack-mann H-H, Olek K. A G₊₃-to-T donor splice site mutation leads to skipping of exon 50 in von Willebrand factor mRNA. Genomics 1994; 24: 190-1.
• 24 Nichols WC, Lyons SE, Harrison JS, Cody RL, Ginsburg D. Severe von Willebrand disease due to a defect at the level of von Willebrand factor mRNA expression: detection by exonic PCR-restriction fragment length polymorphism analysis. Proc Natl Acad Sci USA 1991; 88: 3857-61.
• 25 Eikenboom JCJ, Reitsma PH, Peerlinck KMJ, Briët E. Recessive inheritance of von Willebrand’s disease type I. Lancet 1993; 341: 982-6.
• 26 Peerlinck K, Eikenboom JCJ, Ploos van Amstel HK, Sangtawesin W, Arnout J, Reitsma PH, Vermylen J, Briët E. A patient with von Willebrand’s disease characterized 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 1992; 80: 358-63.
• 27 Cacheris PM, Nichols WC, Ginsburg D. Molecular characterization of a unique von Willebrand disease variant. A novel mutation affecting von Willebrand factor/factor VIII interaction. J Biol Chem 1991; 266: 13499-502.
• 28 Kroner PA, Friedman KD, Fahs SA, Scott JP, Montgomery RR. Abnormal binding of factor VIII is linked with the substitution of glutamine for argi-nine 91 in von Willebrand factor in a variant form of von Willebrand disease. J Biol Chem 1991; 266: 19146-9.
• 29 Lavergne JM, Piao Y, Ribba AS, Girma JP, Siguret V, Piétu G, Boyer-Neumann C, Schandelong A, Bahnak BR, Meyer D. Functional analysis of the Arg91Gln substitution in the factor VIII binding domain of von Willebrand factor demonstrates variable phenotypic expression. Thromb Haemost 1993; 70: 691-6.
• 30 Siguret V, Lavergne J-M, Chérel G, Boyer-Neumann C, Ribba A-S, Bahnak BR, Meyer D, Piétu G. A novel case of compound heterozygosity with “Normandy”/type I von Willebrand disease (vWD). Direct demonstration of the segregation of one allele with a defective expression at the mRNA level causing type I vWD. Hum Genet 1994; 93: 95-102.
• 31 Zhang ZP, Blombäck M, Nyman D, Anvret M. Mutations of von Wille brand factor gene in families with von Willebrand disease in the Åland Is lands. Proc Natl Acad Sci USA 1993; 90: 7937-40.
• 32 Eikenboom JCJ, Matsushita T, Reitsma PH, Tuley EA, Castaman G, Briët E, Sadler JE. Dominant type 1 von Willebrand disease caused by mutated cysteine residues in the D3 domain of von Willebrand factor. Blood 1996; 88: 2433-41.
• 33 Caekebeke-Peerlinck KM, Bakker E, Briët E. An infrequent DNA polymorphism associated with severe von Willebrand’s disease. Br J Haematol 1990; 75: 78-81.
• 34 Mancuso DJ, Tuley EA, Westfield LA, Worrall 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.
• 35 Castaman G, Lattuada A, Mannucci PM, Rodeghiero F. Factor VIII:C increases after desmopressin in a subgroup of patients with autosomal recessive severe von Willebrand disease. Br J Haematol 1995; 89: 147-51.
• 36 Mannucci PM, Lattuada A, Castaman G, Lombardi R, Colibretti ML, Ciavarella N, Rodeghiero F. Heterogeneous phenotypes of platelet and plasma von Willebrand factor in obligatory heterozygotes for severe von Willebrand disease. Blood 1989; 74: 2433-6.
• 37 Ruggeri ZM, Mannucci PM, Bader R, Barbui T. Factor VIII-related properties in platelets from patients with von Willebrand’s disease. J Lab Clin Med 1978; 91: 132-40.
• 38 Italian Working Group.. Spectrum of von Willebrand’s Disease: a study of 100 cases. Br J Haematol 1977; 35: 101-12.
• 39 Mancuso DJ, Tuley EA, Westfield LA, Lester-Mancuso TL, Le Beau MM, Sorace JM, Sadler JE. Human von Willebrand factor gene and pseudogene: structural analysis and differentiation by polymerase chain reaction. Biochemistry 1991; 30: 253-69.
• 40 Zhang ZP, Deng LP, Blomback M, Anvret M. Dinucleotide repeat polymorphism in the promotor region of the human von Willebrand factor gene (vWF gene). Hum Mol Genet 1992; 1: 780.
• 41 Peake IR, Bowen D, Bignell P, Liddell MB, Sadler JE, Standen G, Bloom AL. 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 1990; 76: 555-61.
• 42 Ploos van Amstel HK, Reitsma PH. Tetranucleotide repeat polymorphism in the vWF gene. Nucleic Acids Res 1990; 18: 4957.
• 43 Sadler JE, Ginsburg D. A database of polymorphisms in the von Willebrand factor gene and pseudogene. Thromb Haemost 1993; 69: 185-191.
• 44 Kunkel GR, Graham JB, Fowlkes DM, Lord ST. RsaI polymorphism in von Willebrand factor (vWF) at codon 789. Nucleic Acids Res 1990; 18: 4961.
• 45 Donner M, Holmberg L, Kristoffersson AC, Nilsson IM. 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 1991; 78: 403-7.
• 46 Cooper DN, Krawczak M. The mutational spectrum of single base-pair substitutions causing human genetic disease: patterns and predictions. Hum Genet 1990; 85: 55-74.
• 47 Voorberg J, Fontijn R, Calafat J, Janssen H, Van Mourik JA, Pannekoek H. Assembly and routing of von Willebrand factor variants: the requirements for disulfide-linked dimerization reside within the carboxy-terminal 151 amino acids. J Cell Biol 1991; 113: 195-205.
• 48 Standen GR, Bignell P, Bowen DJ, Peake IR, Bloom AL. Family studies in von Willebrand’s disease by analysis of restriction fragment length polymorphisms and an intragenic variable number tandem repeat (VNTR) sequence. Br J Haematol 1990; 76: 242-9.
• 49 Zhang ZP, Lindstedt M, Blombäck M, Anvret M. Effects of the mutant von Willebrand factor gene in von Willebrand disease. Hum Genet 1995; 96: 388-94.
• 50 Berg LP, Soria JM, Formstone CJ, Morell M, Kakkar VV, Estivill X, Sala N, Cooper DN. Aberrant RNA splicing of the protein C and protein S genes in healthy individuals. Bl Coag Fibrinol 1996; 7: 625-31.
• 51 Chu CS, Trapnell BC, Murtagh JJ, Moss J, Dalemans W, Jallat S, Mercenier A, Pavirani A, Lecocq JP, Cutting GR, Guggino WB, Crystal RG. Variable deletion of exon 9 coding sequences in cystic fibrosis transmembrane conductance regulator gene mRNA transcripts in normal bronchial epithelium. EMBO J 1991; 10: 1355-63.
• 52 Schneppenheim R, Brassard J, Budde U, Krey S, Schwaab R, Oldenburg J. Defective dimerization of von Willebrand factor – a new class of mutations in VWD type 2 and 3. Thromb Haemost. 1997 Suppl. 389 (Abstract).
• 53 Marti T, Rosselet SJ, Titani K, Walsh KA. Identification of disulfide-bridged structures within human von Willebrand factor. Biochemistry 1987; 26: 8099-109.
• 54 Eikenboom JCJ, Vink T, Briet E, Sixma JJ, Reitsma PH. Multiple substitutions in the von Willebrand factor gene that mimic the pseudogene sequence. Proc Natl Acad Sci USA 1994; 91: 2221-4.
• 55 Holmberg L, Dent JA, Schneppenheim R, Budde U, Ware J, Ruggeri ZM. Von Willebrand factor mutation enhancing interaction with platelets in patients with normal multimeric structure. J Clin Invest 1993; 91: 2169-77.
• 56 Ruggeri ZM, Zimmerman TS. Von Willebrand factor and von Willebrand disease. Blood 1987; 70: 895-904.
• 57 Eikenboom JCJ, Reitsma PH, Briet E. Seeming homozygosity in type-IIB von Willebrand’s disease due to a polymorphism within the sequence of a commonly used primer. Ann Hematol 1994; 68: 139-41.