Characterization of Partial Gene Deletions in Type III von Willebrand Disease with Alloantibody Inhibitors^[*]

Summary

von Willebrand factor gene deletions were characterized in four patients with severe type III von Willebrand disease and alloantibodies to von Willebrand factor. A PCR-based strategy was used to characterize the boundaries of the deletions. Identical 30 kb von Willebrand factor gene deletions which include exons 33 through 38 were identified in two siblings of one family by this method. A small 5 base pair insertion (CCTGG) was sequenced at the deletion breakpoint. PCR analysis was used to detect the deletion in three generations of the family, including two family members who are heterozygous for the deletion. In a second family, two type III vWD patients, who are distant cousins, share an -56 kb deletion of exons 22 through 43. The identification and characterization of large vWF gene deletions in these type III vWD patients provides further support for the association between large deletions in both von Willebrand factor alleles and the development of inhibitory alloantibodies.

• References

• 1 Sadler JE. von Willebrand disease. In: The Metabolic Basis of Inherited Disease. 6th edit Scriver CR, Beaudet AL, Sly WS, Valle D. New York: McGraw-Hill NY; 1989: 2171-2188
• 2 Holmberg L, Nilsson IM. von Willebrand disease. Clin Haematol 1985; 14: 461-468
• 3 Ruggeri ZM, Zimmerman TS. von Willebrand factor and von Willebrand disease. Blood 1987; 70: 895-904
• 4 Mancuso DJ, Tuley EA, Westfield LA, Worrall NK, Shelton-Inloes BB, Sorace JM, Alevy YG, Sadler JE. Structure of the human von Willebrand factor gene. J Biol Chem 1989; 264: 195214-195227
• 5 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: 253-269
• 6 Ginsburg D, Sadler JE. von Willebrand disease: A database of point mutations, insertions, and deletions. Thromb Haemost 1993; 69: 177-184
• 7 Shelton-Inloes BB, Chebab FF, Mannucci PM, Federici AB, Sadler JE. Gene deletions correlate with the development of antibodies in von Willebrand disease. J Clin Invest 1987; 79: 1439-1465
• 8 Ngo K, Glotz VT, Koziol JA, Lynch DC, Gitschier J, Ranieri RP, Ciavarel-la N, Ruggeri AM, Zimmerman TS. Homozygous and heterozygous deletions of the von Willebrand factor gene in patients and carriers of severe von Willebrand’s disease. Proc Nat Acad Sci USA 1988; 85: 2753-2757
• 9 Peake IR, Liddell CB, Moodie P, Standen G, Mancuso DJ, Tuley EA, Westfield LA, Sorace JM, Sadler JE, Verwije CL, Bloom AL. Severe type III von Willebrand’s disease caused by deletion of exon 42 of the von Wille-brand factor gene: Family studies that identify carriers of the condition and a compound heterozygous individual. Blood 1990; 75: 654-661
• 10 Bemardi F, Marchetti G, Guerra S, Casanato A, Gemmati D, Patracchini P, Ballerini G, Conconi F. A de novo and heterozygous gene deletion causing a variant of von Willebrand disease. Blood 1990; 75: 677-683
• 11 Nichols WC, Lyons SE, Flarrison JS, Cody RL, Ginsburg D. Severe von Willebrand’s disease due to a defect at the level of von Willebrand factor mRNA expression: detection by exonic PCR-restriction fragment polymorphism analysis. Proc Natl Acad Sci USA 1991; 88: 3857-3861
• 12 Bahnak BR, Lavergne J-M, Rothschild C, Meyer D. A stop codon in a patient with severe type III von Willebrand disease. Blood 1991; 78: 1148-1149
• 13 Eikenboom JC, van Amstel HKP, Reitsma PH, Briet 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: 448-454
• 14 Zhang ZP, Lindstedt M, Falk G, Blomback 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: 850-858
• 15 Lavergne JM, Bahnak BR, Rothschild C, Meyer D. Analysis of the von Willebrand factor gene for nonsense mutations in patients with type III and type I von Willebrand’s disease. Thromb Haemost 1991; 65: 737-741
• 16 Mannucci PM, Cattaneo M. Alloantibodies in congenital von Willebrand’s disease. Res Clin Lab 1991; 21: 119-125
• 17 Lopez-Fernandez MF, Martin R, Lopez-Berges C, Ramos F, de Bosch N, Battle J. Further specificity characterization of von Willebrand factor inhibitors developed in two patients with severe von Willebrand disease. Blood 1988; 72: 116-120
• 18 Maragall S, Castillo R, Ordinas A, Liendo F, Rodriguez M. Inhibition of von Willebrand factor in Willebrand’s disease. Thromb Res 1979; 14: 495-500
• 19 Grunebaum L, Cazenave J-P, Camerino G, Kloepfer C, Mandel J-L, Tol-stoshev P, Jaye M, De la Salle H, Lecocq J-P. Carrier detection of hemophilia B by using restriction site polymorphism associated with the coagulation factor IX gene. J Clin Invest 1984; 73: 1491-1495
• 20 Saiki RK, Gelfand DH, Stoffel S, Scharf SJ, Huguchi R, Horn GT, Mullis KB, Erilich HA. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science 1988; 239: 487-491
• 21 Chen EY, Seeburg PH. Supercoil sequencing: A fast and simple method for sequencing plasmid DNA. DNA(NY) 1985; 4: 165-170
• 22 Sanger F, Nicklen S, Coulson AR. DNA sequencing with chain terminating inhibitors. Proc Natl Acad Sci USA 1977; 74: 5463-5467
• 23 Biggin MD, Gibson TJ, Hong GF. Buffer gradient gels and 35S label as an aid to rapid DNA sequencing determination. Proc Natl Acad Sci USA 1983; 80: 3963-3965
• 24 Mohrenweiser HW, Jonew IM. Review of the molecular characteristics of gene mutations of the germline and somatic cells of the human. Mutation Res 1990; 231: 87-108
• 25 Lehrman MA, Russell DW, Goldstein JW, Brown MSL. Alu-alu recombination deletes splice acceptor sites and produces secreted low lipoprotein receptor in a subject with Familial Hypercholesterolemia. J Biol Chem 1987; 262: 3354-3361
• 26 Hobbs HH, Brown MS, Goldstein JL, Russell DW. Deletion of exon encoding cysteine-rich repeat of low density lipoprotein receptor alters its binding specificity in a subject with familial hypercholesterolemia. J Biol Chem 1986; 261: 13114-13120
• 27 Vnencak-Jones CL, Phillips JA. Hot spots for growth hormone gene deletions in homologous regions outside of alu repeats. Science 1990; 250: 1745-1748
• 28 Rearden A, Magnet A, Kudo S, Fukuda M. Glycophorin B and glycophorin E gene arose from the glycophorin A ancestral gene via duplications during primate evolution. J Biol Chem 1993; 268: 2260-2267
• 29 Efstratiadis A, Posakony JW, Maniatis T, Lawn RM, O’Connell C, Spritz RA, De Riel JK, Forget BG, Weissman SM, Slightom JL, Blechl AE, Smithies O, Baralle FE, Shoulders CC, Proudfoot NJ. The structure and evolution of the human (3-globin gene family. Cell 1980; 21: 653-668
• 30 Kleckner N. Transposable elements in prokaryotes. Annu Rev Genet 1981; 15: 344-404
• 31 Simon P, Decoster C, Brocas H, Schwers J, Vassart G. Absence of human chorionic somatomammotropin during pregnancy associated with two types of gene deletion. Hum Genet 1986; 74: 235-238
• 32 Amor M, Parker KL, Globerman H, New MI, White PC. Mutation in the CYP21B gene (Ile-1720Asn) causes steroid 21-hydroxylase deficiency. Proc Natl Acad Sci USA 1988; 85: 1600-1604
• 33 Tsapis A, Bentaboulet M, Pellet P, Mihaesco E, Thierry D, Seligmann M, Brouet JC. The productive gene for a-U chain disease protein mal is highly modified by insertion-deletion processes. J Immunol 1989; 143: 3821-3827
• 34 Nalbantoglu J, Miles C, Meuth M. Insertion of unique and repetitive DNA fragments into the aprt locus of hamster cells. J Mol Biol 1988; 200: 449-459