Type 2A (IIH) von Willebrand disease is due to mutations that affect von Willebrand factor multimerization

Luciano Baronciani, A. B. Federici, M. Punzo, M. Solimando, G. Cozzi, S. La Marca, V. Rubini, M. T. Canciani, P. M. Mannucci

Research output: Contribution to journalArticle

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Abstract

Background: Type IIH von Willebrand disease was reported 20 years ago as a novel variant characterized by the loss of the largest multimers in plasma and platelets and absence of the typical triplet structure. Objectives and methods: The propositus and his daughter have been reinvestigated and characterized at the molecular level. The identified mutations were expressed in COS-7 cells to evaluate the mechanism of this variant. Results and Discussion: The propositus had normal von Willebrand factor (VWF):ristocetin cofactor activity (RCo) and high VWF antigen (VWF:Ag) values, with a low VWF:RCo/VWF:Ag ratio (0.51). No abnormalities were found in his daughter, except for the reduced triplet structure in plasma VWF and diminished ultralarge VWF (ULVWF) multimers in platelets. Three mutations were identified in the propositus: 604C>T (R202W), 4748G>A (R1583Q), and 2546G>A (C849Y). The amounts of secreted recombinant VWF (rVWF) were apparently increased for R202W (130%), R202W-R1583Q (131%), and R202W-R1583Q/WT (121%), reduced for C849Y (72%) and C849Y/WT (83%), and normal for R1583Q (107%) and R202W-R1583Q/C849Y (102%). In cell lysates, higher values were found in association with the C849Y mutation. A normal multimeric pattern was found in R1583Q rVWF, mainly dimers in R202W rVWF, and intermediate molecular weight multimers in C849Y rVWF. Hybrid R202W-R1583Q/WT and C849Y/WT rVWFs had a nearly normal multimeric pattern, whereas in hybrid R202W-R1583Q/C849Y rVWF there was a loss of large/intermediate multimers. Conclusions: The propositus phenotype seems to be due to mutations R202W and C849Y, both affecting the VWF multimerization process and, for C849Y rVWF, intracellular survival. The absent triplet multimeric structure in the propositus and its reduction in his daughter appears to be related to the lack of ULVWF multimers, which mainly contribute to the formation of satellite bands.

Original languageEnglish
Pages (from-to)1114-1122
Number of pages9
JournalJournal of Thrombosis and Haemostasis
Volume7
Issue number7
DOIs
Publication statusPublished - 2009

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Type 2 von Willebrand Disease
von Willebrand Factor
Mutation
Blood Platelets
von Willebrand Diseases
COS Cells

Keywords

  • Expression study
  • Type 2A
  • Type IIH
  • VonWillebrand disease

ASJC Scopus subject areas

  • Hematology

Cite this

Type 2A (IIH) von Willebrand disease is due to mutations that affect von Willebrand factor multimerization. / Baronciani, Luciano; Federici, A. B.; Punzo, M.; Solimando, M.; Cozzi, G.; La Marca, S.; Rubini, V.; Canciani, M. T.; Mannucci, P. M.

In: Journal of Thrombosis and Haemostasis, Vol. 7, No. 7, 2009, p. 1114-1122.

Research output: Contribution to journalArticle

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title = "Type 2A (IIH) von Willebrand disease is due to mutations that affect von Willebrand factor multimerization",
abstract = "Background: Type IIH von Willebrand disease was reported 20 years ago as a novel variant characterized by the loss of the largest multimers in plasma and platelets and absence of the typical triplet structure. Objectives and methods: The propositus and his daughter have been reinvestigated and characterized at the molecular level. The identified mutations were expressed in COS-7 cells to evaluate the mechanism of this variant. Results and Discussion: The propositus had normal von Willebrand factor (VWF):ristocetin cofactor activity (RCo) and high VWF antigen (VWF:Ag) values, with a low VWF:RCo/VWF:Ag ratio (0.51). No abnormalities were found in his daughter, except for the reduced triplet structure in plasma VWF and diminished ultralarge VWF (ULVWF) multimers in platelets. Three mutations were identified in the propositus: 604C>T (R202W), 4748G>A (R1583Q), and 2546G>A (C849Y). The amounts of secreted recombinant VWF (rVWF) were apparently increased for R202W (130{\%}), R202W-R1583Q (131{\%}), and R202W-R1583Q/WT (121{\%}), reduced for C849Y (72{\%}) and C849Y/WT (83{\%}), and normal for R1583Q (107{\%}) and R202W-R1583Q/C849Y (102{\%}). In cell lysates, higher values were found in association with the C849Y mutation. A normal multimeric pattern was found in R1583Q rVWF, mainly dimers in R202W rVWF, and intermediate molecular weight multimers in C849Y rVWF. Hybrid R202W-R1583Q/WT and C849Y/WT rVWFs had a nearly normal multimeric pattern, whereas in hybrid R202W-R1583Q/C849Y rVWF there was a loss of large/intermediate multimers. Conclusions: The propositus phenotype seems to be due to mutations R202W and C849Y, both affecting the VWF multimerization process and, for C849Y rVWF, intracellular survival. The absent triplet multimeric structure in the propositus and its reduction in his daughter appears to be related to the lack of ULVWF multimers, which mainly contribute to the formation of satellite bands.",
keywords = "Expression study, Type 2A, Type IIH, VonWillebrand disease",
author = "Luciano Baronciani and Federici, {A. B.} and M. Punzo and M. Solimando and G. Cozzi and {La Marca}, S. and V. Rubini and Canciani, {M. T.} and Mannucci, {P. M.}",
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T1 - Type 2A (IIH) von Willebrand disease is due to mutations that affect von Willebrand factor multimerization

AU - Baronciani, Luciano

AU - Federici, A. B.

AU - Punzo, M.

AU - Solimando, M.

AU - Cozzi, G.

AU - La Marca, S.

AU - Rubini, V.

AU - Canciani, M. T.

AU - Mannucci, P. M.

PY - 2009

Y1 - 2009

N2 - Background: Type IIH von Willebrand disease was reported 20 years ago as a novel variant characterized by the loss of the largest multimers in plasma and platelets and absence of the typical triplet structure. Objectives and methods: The propositus and his daughter have been reinvestigated and characterized at the molecular level. The identified mutations were expressed in COS-7 cells to evaluate the mechanism of this variant. Results and Discussion: The propositus had normal von Willebrand factor (VWF):ristocetin cofactor activity (RCo) and high VWF antigen (VWF:Ag) values, with a low VWF:RCo/VWF:Ag ratio (0.51). No abnormalities were found in his daughter, except for the reduced triplet structure in plasma VWF and diminished ultralarge VWF (ULVWF) multimers in platelets. Three mutations were identified in the propositus: 604C>T (R202W), 4748G>A (R1583Q), and 2546G>A (C849Y). The amounts of secreted recombinant VWF (rVWF) were apparently increased for R202W (130%), R202W-R1583Q (131%), and R202W-R1583Q/WT (121%), reduced for C849Y (72%) and C849Y/WT (83%), and normal for R1583Q (107%) and R202W-R1583Q/C849Y (102%). In cell lysates, higher values were found in association with the C849Y mutation. A normal multimeric pattern was found in R1583Q rVWF, mainly dimers in R202W rVWF, and intermediate molecular weight multimers in C849Y rVWF. Hybrid R202W-R1583Q/WT and C849Y/WT rVWFs had a nearly normal multimeric pattern, whereas in hybrid R202W-R1583Q/C849Y rVWF there was a loss of large/intermediate multimers. Conclusions: The propositus phenotype seems to be due to mutations R202W and C849Y, both affecting the VWF multimerization process and, for C849Y rVWF, intracellular survival. The absent triplet multimeric structure in the propositus and its reduction in his daughter appears to be related to the lack of ULVWF multimers, which mainly contribute to the formation of satellite bands.

AB - Background: Type IIH von Willebrand disease was reported 20 years ago as a novel variant characterized by the loss of the largest multimers in plasma and platelets and absence of the typical triplet structure. Objectives and methods: The propositus and his daughter have been reinvestigated and characterized at the molecular level. The identified mutations were expressed in COS-7 cells to evaluate the mechanism of this variant. Results and Discussion: The propositus had normal von Willebrand factor (VWF):ristocetin cofactor activity (RCo) and high VWF antigen (VWF:Ag) values, with a low VWF:RCo/VWF:Ag ratio (0.51). No abnormalities were found in his daughter, except for the reduced triplet structure in plasma VWF and diminished ultralarge VWF (ULVWF) multimers in platelets. Three mutations were identified in the propositus: 604C>T (R202W), 4748G>A (R1583Q), and 2546G>A (C849Y). The amounts of secreted recombinant VWF (rVWF) were apparently increased for R202W (130%), R202W-R1583Q (131%), and R202W-R1583Q/WT (121%), reduced for C849Y (72%) and C849Y/WT (83%), and normal for R1583Q (107%) and R202W-R1583Q/C849Y (102%). In cell lysates, higher values were found in association with the C849Y mutation. A normal multimeric pattern was found in R1583Q rVWF, mainly dimers in R202W rVWF, and intermediate molecular weight multimers in C849Y rVWF. Hybrid R202W-R1583Q/WT and C849Y/WT rVWFs had a nearly normal multimeric pattern, whereas in hybrid R202W-R1583Q/C849Y rVWF there was a loss of large/intermediate multimers. Conclusions: The propositus phenotype seems to be due to mutations R202W and C849Y, both affecting the VWF multimerization process and, for C849Y rVWF, intracellular survival. The absent triplet multimeric structure in the propositus and its reduction in his daughter appears to be related to the lack of ULVWF multimers, which mainly contribute to the formation of satellite bands.

KW - Expression study

KW - Type 2A

KW - Type IIH

KW - VonWillebrand disease

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