Download PDF
Thromb Haemost 1998; 79(04): 718-722
DOI: 10.1055/s-0037-1615051
Rapid Communication
Schattauer GmbH

Ins405AsnPro Mutation in the von Willebrand Factor Propeptide in Recessive Type 2A (IIC) von Willebrand’s Disease

L. Holmberg
1   From the Department of Paediatrics Lund University, Sweden
,
D. Karpman
1   From the Department of Paediatrics Lund University, Sweden
,
C. Isaksson
1   From the Department of Paediatrics Lund University, Sweden
,
A. C. Kristoffersson
1   From the Department of Paediatrics Lund University, Sweden
,
S. Lethagen
2   From the Department of Coagulation Disorders, Lund University, Sweden
,
R. Schneppenheim
3   From the Department of Paediatrics, Kiel, Germany
› Author Affiliations
Further Information

Publication History

Received 12 September 1997

Accepted after revision 13 November 1997

Publication Date:
07 December 2017 (online)

    Permissions and Reprints

Summary

The molecular defects of the von Willebrand factor (vWF) have been studied in the patient in whom the von Willebrand disease phenotype IIC was originally described. A six nucleotide insert, AATCCC, was found in exon 11 of the vWF gene, predicting the insertion of the amino acids asparagine and proline between phenylala-nine 404 and threonine 405 of the vWF propeptide. The mutation was present in one allele. Analysis of amplification products derived from platelet vWF mRNA showed the other allele to be silent. The patient is thus a compound heterozygote for a null allele and the IIC allele, in accord with the recessive mode of inheritance of the IIC phenotype. Family studies indicated the IIC mutation to have occurred de novo, possibly as a result of a duplication event. In vitro mutagenesis and expression in COS-7 cells confirmed the detrimental effect of the mutation on vWF multimer assembly. Taken together with those of earlier studies the present findings suggest that the IIC phenotype may well be exclusively caused by mutations which result in changes of the amino acid sequence in certain regions of the vWF propeptide. Although in the recently revised classification of von Willebrand’s disease variants, the IIC type is included in the 2A category, obviously it constitutes a very distinct subtype.

 

  • References

  • 1 Sadler JE, Shelton-Inloes BB, Sorace JM, Harlan JM, Titani K, Davie EW. Cloning and characterization of two cDNAs coding for human von Willebrand factor. Proc Natl Acad Sci USA 1985; 82: 6394-8.
    CrossrefPubMedGoogle Scholar
  • 2 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 localization. Science 1985; 228: 1401-6.
    CrossrefPubMedGoogle Scholar
  • 3 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.
    PubMedGoogle Scholar
  • 4 Sadler JE, Matsushita T, Dong Z, Tuley EA, Westfield LA. Molecular mechanism and classification of von Willebrand disease. Thromb Haemost 1995; 74: 161-6.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 Ruggeri ZM, Nilsson IM, Lombardi R, Holmberg L, Zimmerman TS. Aberrant multimeric structure of von Willebrand factor in a new variant of von Willebrand’s disease (type IIC). J Clin Invest 1982; 70: 1124-7.
    CrossrefPubMedGoogle Scholar
  • 6 Mannucci PM, Lombardi R, Pareti FI, Solinas S, Mazzucconi MG, Mariani G. A variant of von Willebrand´s disease characterized by recessive inheritance and missing triplet structure of von Willebrand factor multimers. Blood 1983; 62: 1000-5.
    PubMedGoogle Scholar
  • 7 Mazurier C, Mannucci PM, Parquet-Gernez A, Goudemand M, Meyer D. Investigation of a case of subtype IIC von Willebrand disease: characterization of the variability of this subtype. Am J Hematol 1986; 22: 301-11.
    CrossrefPubMedGoogle Scholar
  • 8 Battle J, Lopez-Fernandez MF, Fernandez Villamor A, Lopez Berges C, Zimmerman TS. Multimeric pattern discrepancy between platelet and plasma von Willebrand factor in type IIC von Willebrand disease. Am J Hematol 1986; 22: 87-8.
    CrossrefPubMedGoogle Scholar
  • 9 Gaucher C, Diéval J, Mazurier C. Characterization of von Willebrand factor gene defects in two unrelated patients with type IIC von Willebrand disease. Blood 1994; 84: 1024-30.
    PubMedGoogle Scholar
  • 10 Gaucher C, Mazurier C. Phenotype IIC von Willebrand disease: the expression of three mutant recombinant von Willebrand factors (vWF) confirms the importance of the D2 domain of vWF propeptide in the multimer assembly process. Br J Haematol 1996; 93 (Suppl. 02) 15 (abstract).
    CrossrefPubMedGoogle Scholar
  • 11 Mazurier C, Uno H, Yamasaki T, Gaucher C. Identification of a new von Willebrand factor propeptide mutation (N528S) responsible for phenotype IIC von Willebrand disease. Thromb Haemost. 1997 Suppl.: 388.
    PubMedGoogle Scholar
  • 12 Schneppenheim R, Thomas KB, Krey S, Budde U, Jessat U, Sutor AH, Zieger B. Identification of a candidate missense mutation in a family with von Willebrand disease type IIC. Hum Genet 1995; 95: 681-6.
    PubMedGoogle Scholar
  • 13 Blin N, Stafford DW. A general method for isolation of high molecular weight DNA from eukaryocytes. Nucl Acid Res 1976; 3: 2303-9.
    CrossrefPubMedGoogle Scholar
  • 14 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.
    CrossrefPubMedGoogle Scholar
  • 15 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.
    CrossrefPubMedGoogle Scholar
  • 16 Chomczynski P, Sacchi N. Single step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 1987; 162: 156-9.
    PubMedGoogle Scholar
  • 17 Sadler JE, Ginsburg D. A database of polymorphisms in the von Willebrand factor gene and pseudogene. Thromb Haemost 1993; 69: 185-91.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 18 Lyons SE, Bruck ME, Bowie EJW, Ginsburg D. Impaired intracellular transport produced by a subset of type IIA von Willebrand disease mutations. J Biol Chem 1992; 267: 4424-30.
    PubMedGoogle Scholar
  • 19 Kriegler M. Gene transfer and expression. A laboratory manual. Stockton press; New York, NY: 1990. pp 99-100.
    Google Scholar
  • 20 Ruggeri ZM, Zimmerman TS. Variant von Willebrand’s disease. Characterization of two subtypes by analysis of multimeric composition of factor VIII/von Willebrand factor in plasma and platelets. J Clin Invest 1980; 65: 1318-25.
    CrossrefPubMedGoogle Scholar
  • 21 Verweij CL, Hart M, Pannekoek H. Expression of variant von Willebrand factor (vWF) cDNA in heterologous cells: requirement of the propoly-peptide in vWF multimer formation. EMBO J 1987; 6: 2885-90.
    PubMedGoogle Scholar
  • 22 Mayadas TN, Wagner DD. In vitro multimerization of von Willebrand factor is triggered by low pH. J Biol Chem 1989; 264: 13497-503.
    PubMedGoogle Scholar
  • 23 Marti T, Rösselet SJ, Titani K, Walsh KA. Identification of disulfide-bridged substructures within human von Willebrand factor. Biochemistry 1987; 26: 8099-109.
    CrossrefPubMedGoogle Scholar
  • 24 Dong Z, Thoma RS, Crimmins DL, McCourt DW, Tuley EA, Sadler JE. Disulfide bonds required to assemble functional von Willebrand factor multimers. J Biol Chem 1994; 269: 6753-8.
    PubMedGoogle Scholar
  • 25 Mayadas TN, Wagner DD. Vicinal cysteines in the prosequence play a role in von Willebrand factor multimer assembly. Proc Natl Acad Sci USA 1992; 89: 3531-5.
    CrossrefPubMedGoogle Scholar
  • 26 Shakin-Eshleman SH, Spitalnik SL, Kasturi L. The amino acid at the X position of an Asn-X-Ser sequon is an important determinant of N-linked core-glycosylation efficiency. J Biol Chem 1996; 271: 6363-6.
    CrossrefPubMedGoogle Scholar
  • 27 Zimmerman TS, Dent JA, Ruggeri ZM, Nannini LH. Subunit composition of plasma von Willebrand factor. J Clin Invest 1986; 77: 947-51.
    CrossrefPubMedGoogle Scholar
  • 28 Schneppenheim R, Brassard J, Krey S, Budde U, Kunicki TJ, Holmberg L, Ware J, Ruggeri ZM. Defective dimerization of von Willebrand factor subunits due to a Cys → Arg mutation in type IID von Willebrand disease. Proc Natl Acad Sci USA 1996; 93: 3581-6.
    CrossrefPubMedGoogle Scholar
  • 29 Schneppenheim R, Budde U, Krey S, Drewke E. Identification of a single base deletion (DC 8565/8566) in a patient with von Willebrand disease type 2A (subtype IIE). Blood 1996; 88 (Suppl. 01) 326a.
    PubMedGoogle Scholar