Discrepancy between IIA phenotype and IIB genotype in a patient with a variant of von Willebrand disease

Abstract

Type IIA and IIB von Willebrand disease (vWD) result from qualitative abnormalities of von Willebrand factor (vWF) characterized by an absence in plasma of high molecular weight vWF multimers and an abnormal reactivity of vWF towards platelet glycoprotein (GP) Ib, which is decreased in type IIA and increased in type IIB. In this report, we describe the case of a patient having a IIA vWD phenotype associated with an intermittent thrombocytopenia atypical in this subtype but observed in type IIB vWD. The patient plasma vWF showed an absence of high molecular weight and intermediate multimers and had a decreased binding capacity to GPIb. The affinity of botrocetin was normal for plasma vWF from the propositus. Analysis of the propositus vWF gene showed the presence of a substitution Val 551 to Phe of the mature vWF subunit. This mutation is localized within a 509–695 disulphide loop of the vWF that plays an important role in the binding to GPIb and is where most of the molecular defects described so far were associated with type-IIB vWD. We have reproduced the Val 551 Phe substitution onto the vWF cDNA, expressed it in COS-7 cells, and performed structural and functional analysis of the mutant recombinant protein (rvWFPhe 551). The rvWFPhe 551 had a normal multimeric structure and showed the capacity to spontaneously interact with GPIb. Botrocetin had a decreased affinity for rvWFPhe 551. In conclusion, the Val 551 Phe mutation modifies the affinity of vWF for platelet GPIb, as does a type IIB mutation, and may be responsible for the thrombocytopenia of the patient and the clearance of the high molecular weight and intermediate-sized multimers of vWF from the plasma. The study of the rvWFPhe 551 has confirmed the discrepancy between the IIA phenotype and the IIB genotype of the patient.

The arginine-552-cysteine (R1315C) mutation within the A1 loop of von Willebrand factor induces an abnormal folding with a loss of function resulting in type 2A–like phenotype of von Willebrand disease: study of 10 patients and mutated recombinant von Willebrand factor

“…Indeed, 5 mutations-C509R, C509G, R545C, valine (V)551F, and V553M (methionine)-have been identified within the A1 disulfide loop in patients with an apparent 2A phenotype. 18,[20][21][22] However, the corresponding mutated rvWF exhibited an increased affinity for platelet GpIb, as observed in patients with type 2B vWD. 21,[23][24][25] Moreover, the study of platelet vWF in a patient with the V553M mutation showing an increased affinity for GpIb is also in favor of type 2B vWD.…”

“…18,[20][21][22] However, the corresponding mutated rvWF exhibited an increased affinity for platelet GpIb, as observed in patients with type 2B vWD. 21,[23][24][25] Moreover, the study of platelet vWF in a patient with the V553M mutation showing an increased affinity for GpIb is also in favor of type 2B vWD. 22 In the present paper we report the identification of an arginineto-cysteine mutation at position 552 of the mature vWF subunit (R1315C in the preprovWF) in 10 patients from 6 families showing a 2A-like phenotype.…”

“…It is interesting to note that the R552C substitution is localized between V551 and V553, which have been found mutated in patients with either 2B or 2A phenotype 18,21,22,43,44 but 2B genotype. The latter discrepancy may be explained by the spontaneous binding to platelets of plasma intermediate-MW and HMW multimers, which are cleared in vivo from the circulation.…”

The molecular biology of von Willebrand disease

“…Molecular modelling of the A2 domain indicates that these mutations are likely to affect VWF protein folding to some extent (Jenkins et al., 1998). Several amino acid substitutions, C1272R (Cys509Arg) (Lavergne et al., 1992) and V1314F (Val551Phe) (Ribba et al., 1994) and other mutations, now confirmed by expression studies, have been identified in the anterior region of exon 28 within the A1 domain in individual cases of type 2A VWD (Meyer et al., 1997; Ribba et al., 1999). In addition, a duplication event encompassing S1352‐A1386 (Ser589‐Ala623 of the mature subunit) and an in‐frame deletion of exons 26–34 have also been reported to result in a type 2A VWD phenotype (Bernardi et al., 1990; Bernardi et al., 1993; Gaucher et al., 1995a; Meyer et al., 1997).…”

von Willebrand Jürgens Syndrom Typ IIB als Ursache neonataler Thrombocytopenie

“…beschreibungen von Patienten, die ebenfalls vom Phänotyp der Multimerenanalyse und einer verminderten Affinität ihres vWF zum Gp Ib der Thrombozyten als Typ IIA eingestuft wurden, zusätzlich jedoch episodische Thrombopenien aufwiesen. Hier konnte in einem Fall eine Punktmutation nachgewiesen werden, deren Locus typisch für die mit einem Typ IIB assoziierten Genmutationen war (9).…”