Variable content of von Willebrand factor mutant monomer drives the phenotypic variability in a family with von Willebrand disease

Chen, Junmei; Hinckley, Jesse D.; Haberichter, Sandra L.; Jacobi, Paula M.; Montgomery, Robert R.; Flood, Veronica H.; Wong, Randall; Interlandi, Gianluca; Chung, Dominic W.; López, José A.; Paola, Jorge Di

doi:10.1182/blood-2014-11-613935

Cited by 17 publications

(13 citation statements)

References 30 publications

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“…A DDAVP trial previously performed on a patient with a C1272S mutation reported by Penas et al in which platelet counts dropped from 200*10 9 L −1 to 157*10 9 L −1 at 30 min post-DDAVP treatment even though VWF:Ag, VWF:RCo, RIPA and presence of high molecular weight multimers were deficient relative to normal throughout the trial [15]. Relative to the patients reported here, DDAVP treatment of the C1272S patient only modestly reduced the platelet count indicating that perhaps the expression of the mutation was variable as has been observed with other type 2M/2A VWD patients with the same genotype within the same family [27]. Recombinant VWF studies using ristocetin induced platelet binding have previously indicated some gain- or loss-of-function dependency on which cysteine was mutated [11] and others have demonstrated that Cys->Ala mutations can abolish RIPA [12] indicating that ristocetin based assays are not functionally effective with mutations that alter the disulfide bonding of A1 in VWF.…”

Section: Resultsmentioning

confidence: 75%

Enhanced Local Disorder in a Clinically Elusive von Willebrand Factor Provokes High-Affinity Platelet Clumping

Tischer

Machha

Frontroth

et al. 2017

Journal of Molecular Biology

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Mutation of the cysteines forming the disulfide loop of the platelet GPIbα adhesive A1 domain of von Willebrand factor causes quantitative VWF deficiencies in the blood and von Willebrand disease. We report two cases of transient severe thrombocytopenia induced by DDAVP-treatment. Cys1272Trp and Cys1458Tyr mutations identified by genetic sequencing implicate an abnormal gain-of-function phenotype, evidenced by thrombocytopenia, that quickly relapses back to normal platelet counts and deficient plasma VWF. Using surface plasmon resonance, analytical rheology, and hydrogen-deuterium exchange mass spectrometry (HXMS), we decipher mechanisms of A1-GPIbα mediated platelet adhesion and resolve dynamic secondary structure elements that regulate the binding pathway. Constrained by the disulfide, conformational selection between weak and tight binding states of A1 takes precedence and drives normal platelet adhesion to VWF. Less restrained through mutation, loss of the disulfide preferentially diverts binding through an induced-fit disease pathway enabling high-affinity GPIbα binding and firm platelet adhesion to a partially disordered A1 domain. HXMS reveals a dynamic asymmetry of flexible and ordered regions common to both variants indicating that the partially disordered A1 lacking the disulfide retains native-like structural dynamics. Both binding mechanisms share common structural and thermodynamic properties, but the enhanced local disorder in the disease state perpetuates high-affinity platelet agglutination, characteristic of type 2B VWD, upon DDAVP-stimulated secretion of VWF leading to transient thrombocytopenia and a subsequent deficiency of plasma VWF, characteristic of type 2A VWD.

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Section: Resultsmentioning

confidence: 75%

Enhanced Local Disorder in a Clinically Elusive von Willebrand Factor Provokes High-Affinity Platelet Clumping

Tischer

Machha

Frontroth

et al. 2017

Journal of Molecular Biology

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“…One possibility is that the low score observed in several members of the families reported here is due to a real lack of bleeding symptoms perhaps owing to a variable multimer structure (multimer information and data not available on all patients) with higher score achievers having a shift to low molecular weight multimers (LMWM) or loss of high molecular weight multimers (HMWM) which are crucial to hemostasis. In a recent study [25] of a 24 member pedigree with VWD type 2 and variable multimer distribution and bleeding, the variability was partially explained on the basis of mutant monomer incorporation in the final multimer structure of plasma VWF. In this family, different individuals carrying the same mutation could be classified as type 1, type 2A, or type 2M.…”

Section: Discussionmentioning

confidence: 99%

Variable bleeding phenotype in an Amish pedigree with von Willebrand disease

et al. 2016

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Through a cross sectional study design, the bleeding phenotype in the Amish in Indiana (IN) and Wisconsin (WI) was described using two different bleeding scores. von Willebrand factor (VWF) testing was performed and bleeding questionnaires from Centers for Disease Control and Prevention (CDC) and European MCMDM-1 (Tosetto bleeding score (BS)) were administered to the IN and WI cohort respectively. Seven hundred and seventy nine subjects were recruited, 17% were diagnosed with VWD based on Ristocetin cofactor, VWF:RCo<30 IU/dl. Majority of the affected (AF), 67%, were tested and had a common mutation c.4120 C>T. The WI AF were much younger at a mean age 15 years vs 26 years in IN AF cohort. The AF subjects had a median VWF:RCo of 13IU/dl with a statistically significant higher median BS 1 vs 0 in the WI AF vs WI Unaffected (UA), 2 vs 1 in the IN AF vs IN UA, P<0.01. Adults had a higher median BS compared to children in the WI and IN cohort, 2 vs 1 and 3 vs 1 respectively (P<0.05) but there was no statistically significant difference in the BS between males and females in either cohort. The common symptoms reported were epistaxis and gingival oozing. BS ≥3 and BS≥4 were observed in 46% of AF IN and 16.6% of AF WI, respectively. There was significant variability in the bleeding phenotype, with an overall low BS in the affected Amish with VWD, despite a unifying mutation.

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“…It is possible that altering the mutant incorporation into VWF multimers could be influencing the proper intracellular multimeric processing of VWF in the cases of R782Q, M771I, Y1146C and T1156M, as well as the function of the VWF multimer once it is secreted from the cell. We have recently shown that increasing the incorporation of a specific mutant VWF into larger VWF multimers may drive the pathogenesis of type 2 VWD; it is possible that a similar mechanism may occur in type 1 VWD (25). …”

Section: Discussionmentioning

confidence: 99%

Mutations in the D′D3 region of VWF traditionally associated with type 1 VWD lead to quantitative and qualitative deficiencies of VWF

White-Adams

Jacobi

et al. 2016

Thrombosis Research

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Type 1 von Willebrand disease (VWD) is characterized by low plasma levels of von Willebrand factor (VWF) and clinical bleeding. Several mechanisms have been described that cause a decrease in plasma VWF levels in VWD, and the goal of this study was to elucidate the pathogenic origins of VWD for a group of mutations in the VWF D’D3 region traditionally associated with type 1 VWD. Varying ratios of mutant-to-wild-type VWF were expressed in two cell lines in order to study the intracellular location, multimer assembly, secretion and function of VWF. We identified four mutants (M771I, Y1146C, T1156M, R782Q) that caused defective intracellular packaging and markedly reduced VWF secretion. Consistent with previous reports, Y1146C and T1156M VWF led to a loss of high molecular weight multimers. In a functional analysis, Y1146C demonstrated a novel FVIII binding defect. Mutations R924W and I1094T were processed normally and did not show abnormal FVIII binding suggesting that other mechanisms such as plasma clearance or platelet binding defects may contribute to the pathogenicity of these mutants.

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Variable content of von Willebrand factor mutant monomer drives the phenotypic variability in a family with von Willebrand disease

Abstract: Key Points VWD is characterized by variable expressivity, even within families with the same VWF mutation. The content of mutant monomers in the final multimeric structure may explain the observed variability.

Cited by 17 publications

References 30 publications

Enhanced Local Disorder in a Clinically Elusive von Willebrand Factor Provokes High-Affinity Platelet Clumping

Enhanced Local Disorder in a Clinically Elusive von Willebrand Factor Provokes High-Affinity Platelet Clumping

Variable bleeding phenotype in an Amish pedigree with von Willebrand disease

Mutations in the D′D3 region of VWF traditionally associated with type 1 VWD lead to quantitative and qualitative deficiencies of VWF

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