Characterization of Three Mutations Causing von Willebrand Disease Type IIA in Five Unrelated Families

Summary

Von Willebrand disease (vWD) type IIA is characterized by decreased ristocetin-induced platelet aggregation, and by the absence from plasma of high molecular weight multimers of von Willebrand factor (vWF). Most mutations causing vWD type IIA are clustered within the A2 domain of the mature vWF subunit that is encoded by exon 28. Using the polymerase chain reaction (PCR), the entire exon 28 from patients with vWD type IIA and normal controls was amplified and sequenced. Three missense mutations were detected that result in the amino acid substitutions Arg(834)→Trp, Gly(742)→Glu, and Ser(743)→Leu. The first mutation occurred independently in three unrelated families; each of the latter mutations was found in one family. By restriction endonuclease analysis and allele-specific oligonucleotide (ASO) hybridization the mutations were confirmed in affected family members and excluded in unaffected members and 50 normal controls. The apparently high frequency of identical independent mutations among patients with vWD type IIA suggests that a precise diagnosis may be possible in a majority of patients using relatively simple recombinant DNA screening assays.

• References

• 1 Girma JP, Meyer D, Verweij CL, Pannekoek H, Sixma JJ. Structure-function relationship of human von Willebrand factor. Blood 1987; 70: 605-611
• 2 Tuddenham EGD, Lane RS, Rotblat F, Johnson AJ, Snape J, Middleton S, Kernoff PBA. Response to infusions of poly electrolyte fractionated human factor VIII concentrate in human hemophilia A and von Willebrand’s disease. Br J Haematol 1982; 52: 259-267
• 3 Ginsburg DR, Handin I, Bonthron DT, Donolon TA, Bruns GAP, Latt SA, Orkin SH. Human von Willebrand Factor (vWF): Isolation of cDNA clones and chromosomal localization. Science (Wash DC) 1985; 228: 1401-1406
• 4 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: 19514-19527
• 5 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: 1459-1465
• 6 Mancuso DJ, Tuley AE, 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
• 7 Ruggeri ZM, Zimmerman TS. Von Willebrand factor and von Willebrand disease. Blood 1987; 70: 895-904
• 8 Ginsburg D, Konkle BA, Gill JC, Montgomery RR, Bockenstedt PL, Johnson TA, Yang AY. Molecular basis of human von Willebrand disease: analysis of platelet von Willebrand factor mRNA. Proc Natl Acad Sci USA 1989; 86: 3723-3727
• 9 Sugiura I, Matsushita T, Tanimoto M, Takamatsu J, Kamiya T, Saito H, Furuya H, Kato Y. The molecular defects in Japanese patients with Type II von Willebrand disease. Thromb Haemostas 1991; 65: 329a
• 10 Lyons SE, Ginsburg D. Type IIA von Willebrand Disease (vWD) due to defective intracellular transport of von Willebrand Factor. J Cell Biol 1990; 111: 464a
• 11 Iannuzzi MC, Hidaka N, Boehnke M, Bruck ME, Hanna WT, Collins FS, Ginsburg D. Analysis of the relationship of von Willebrand disease (vWD) and hereditary hemorrhagic telangiectasia and identification of a potential vWD type IIa mutation (IIe865 to Thr). Am J Hum Genet 1991; 48: 757-763
• 12 Layergne JM, Ribba AS, Bahnak BR, de Paillette L, Derlon A, Meyer D, Pietu G. The use of denaturing gradient gel electrophoresis to detect base changes in the von Willebrand factor gene from type IIA von Willebrand disease patients. Thromb Haemostas 1991; 65: 262a
• 13 Chang HY, Chen Y-P, Chediak JR, Levene RB, Lynch DC. Molecular analysis of von Willebrand factor produced by endothelial cell strains from patients with type IIA von Willebrand disease (vWD). Blood 1989; 74 (Suppl): 131a
• 14 Randi AM, Rabinowitz I, Mancuso DJ, Mannucci PM, Sadler JE. Molecular basis of von Willebrand disease type IIB. Candidate mutations cluster in one disulfide loop between proposed platelet glycoprotein lb binding sequences. J Clin Invest 1991; 87: 1220-1226
• 15 Cooney KA, Nichols WC, Bruck ME, Bahou WF, Shapiro AD, Bowie EJW, Gralnick HR, Ginsburg D. The molecular defect in type IIB von Willebrand disease. Identification of four potential missense mutations within the putative GPIb binding domain. J Clin Invest 1991; 87: 1227-1233
• 16 Ware J, Dent JA, Azuma H, Sugimoto M, Kyrle PA, Yoshioka A, Ruggeri ZM. Identification of a point mutation in type IIB von Willebrand disease illustrating the regulation of von Willebrand factor affinity for the platelet membrane glycoprotein Ib-IX receptor. Proc Natl Acad Sci USA 1991; 88: 2946-2950
• 17 Saiki RK, Gelfand DH, Stoffel S, Scharf SJ, Higuchi R, Horn GT, Mullis KB, Erlich HA. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science (Wash DC) 1988; 239: 487-491
• 18 Maniatis T, Fritsch EF, Sambrook J. Molecular Cloning: A Laboratory Manual. >2nd Ed.. Cold Spring Harbor Lab; Cold Spring Harbor, NY: 1989: 15.29
• 19 Barker D, Schafer M, White R. Restriction sites containing CpG show a higher frequency of polymorphism in human DNA. Cell 1984; 36: 131-138
• 20 Batlle J, Lopez Fernandez MF, Campos M, Justica B, Berges C, Navarro JL. Diaz Cremades JM, Kasper CK, Dent J A, Ruggeri ZM, Zimmerman TS. The heterogeneity of Type IIA von Willebrand’s disease: studies with protease inhibitors. Blood 1986; 68: 1207-1212
• 21 Berkowitz SD, Dent JA, Roberts J, Fujimura Y, Plow EF, Titani K, Ruggeri ZM, Zimmerman TS. Epitope mapping of the von Willebrand factor subunit distinguishes fragments present in normal and type IIA von Willebrand disease from those generated by plasmin. J Clin Invest 1987; 79: 524-531
• 22 Gralnick HR, Williams SB, McKeown LP, Maisonneuve P, Jenneau C, Sultan Y, Rick ME. In vitro correction of the abnormal multimeric structure of von Willebrand factor in Type IIA von Willebrand’s disease. Proc Natl Acad Sci USA 1988; 82: 7652-7656
• 23 Dent JA, Berkowitz DS, Ware J, Kasper CK, Ruggeri ZM. Identification of a cleavage site directing the immunochemical detection of molecular abnormalities in type IIA von Willebrand factor. Proc Natl Acad Sci USA 1990; 87: 6406-6410
• 24 Levene RB, Booyse FM, Chediak JR, Zimmerman TS, Livingston DM, Lynch DC. Expression of abnormal von Willebrand factor by endothelial cells from a patient with Type IIA von Willebrand disease. Proc Natl Acad Sci USA 1987; 84: 6550_4
• 25 Wilbourn BR, Lawrie AS, Rowley M, Bevan DH, Savidge GF, Harrison P. Studies on ultra-high MW vWF in normals and vWD type IIa. Thromb Haemostas 1991; 65: 987a