Identification of a novel point mutation in platelet glycoprotein Ibα, Gly to ser at residue 233, in a Japanese family with platelet-type von Willebrand disease

Y. Matsubara, Mitsuru Murata, K. Sugita, Y. Ikeda

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36 Citations (Scopus)

Abstract

Background: Interaction between platelet glycoprotein (GP)Iba and von Willebrand factor (VWF) has critical roles in both physiological hemostasis and thrombosis. Platelet-type von Willebrand disease (plt-VWD) is a congenital bleeding disorder characterized by gain-of-function mutations of GPIbα. To date, two mutations in GPIbα, G233V and M239V, have been reported in four unrelated families with plt-VWD. Objective: The present study aimed to determine whether G233S of GPIba, a new mutation observed in plt-VWDpa-tients, causes the plt-VWDphenotype and to examine whether conversions to other residues at this position affect VWF binding. Patients and methods: The propositus was a 3-year-old Japanese male. He displayed bleeding symptoms and moderate thrombocytopenia. His brother was similarly affected. Platelets from both patients were analyzed by ristocetin- or shear-induced platelet aggregation. DNA sequencing was performed to analyze the GPIba sequence. We examined the I-labeled VWF binding using a series of recombinant GPIba fragments with different residues at position 233 (G233S, G233A, G233K, and G233D) together with naturally occurring mutations previously reported in patients (G233Vand M239V). Results: Platelet function analysis indicated that platelets from both patients had a typical plt-VWDphenotype. DNA sequen-cing analysis showed a heterozygous mutation of Gly to Ser at residue 233 of GPIba in both patients. The 125I-labeled VWF binding to mutant compared with the wild type displayed three patterns, gain-of-function (G233S, G233V, and M239V), equivalent function (G233A), and loss-of-function (G233K and G233D). Conclusions: The G233S is a molecular basis of plt-VWD, and residue 233 plays critical roles in regulating VWF binding.

Original languageEnglish
Pages (from-to)2198-2205
Number of pages8
JournalJournal of Thrombosis and Haemostasis
Volume1
Issue number10
DOIs
Publication statusPublished - 2003 Oct

Fingerprint

Platelet Glycoprotein GPIb-IX Complex
Platelet Membrane Glycoproteins
von Willebrand Factor
Point Mutation
Mutation
Blood Platelets
Ristocetin
Hemorrhage
Congenital, Hereditary, and Neonatal Diseases and Abnormalities
Hemostasis
DNA Sequence Analysis
Platelet Aggregation
Thrombocytopenia
Sequence Analysis
Siblings
Thrombosis
Platelet type Von Willebrand disease
DNA

Keywords

  • Glycoprotein iba
  • Mutagenesis
  • Platelet-type von willebrand disease

ASJC Scopus subject areas

  • Hematology
  • Medicine(all)

Cite this

@article{7dff86ce377843b1ba4278253f9f12a1,
title = "Identification of a novel point mutation in platelet glycoprotein Ibα, Gly to ser at residue 233, in a Japanese family with platelet-type von Willebrand disease",
abstract = "Background: Interaction between platelet glycoprotein (GP)Iba and von Willebrand factor (VWF) has critical roles in both physiological hemostasis and thrombosis. Platelet-type von Willebrand disease (plt-VWD) is a congenital bleeding disorder characterized by gain-of-function mutations of GPIbα. To date, two mutations in GPIbα, G233V and M239V, have been reported in four unrelated families with plt-VWD. Objective: The present study aimed to determine whether G233S of GPIba, a new mutation observed in plt-VWDpa-tients, causes the plt-VWDphenotype and to examine whether conversions to other residues at this position affect VWF binding. Patients and methods: The propositus was a 3-year-old Japanese male. He displayed bleeding symptoms and moderate thrombocytopenia. His brother was similarly affected. Platelets from both patients were analyzed by ristocetin- or shear-induced platelet aggregation. DNA sequencing was performed to analyze the GPIba sequence. We examined the I-labeled VWF binding using a series of recombinant GPIba fragments with different residues at position 233 (G233S, G233A, G233K, and G233D) together with naturally occurring mutations previously reported in patients (G233Vand M239V). Results: Platelet function analysis indicated that platelets from both patients had a typical plt-VWDphenotype. DNA sequen-cing analysis showed a heterozygous mutation of Gly to Ser at residue 233 of GPIba in both patients. The 125I-labeled VWF binding to mutant compared with the wild type displayed three patterns, gain-of-function (G233S, G233V, and M239V), equivalent function (G233A), and loss-of-function (G233K and G233D). Conclusions: The G233S is a molecular basis of plt-VWD, and residue 233 plays critical roles in regulating VWF binding.",
keywords = "Glycoprotein iba, Mutagenesis, Platelet-type von willebrand disease",
author = "Y. Matsubara and Mitsuru Murata and K. Sugita and Y. Ikeda",
year = "2003",
month = "10",
doi = "10.1046/j.1538-7836.2003.00369.x",
language = "English",
volume = "1",
pages = "2198--2205",
journal = "Journal of Thrombosis and Haemostasis",
issn = "1538-7933",
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TY - JOUR

T1 - Identification of a novel point mutation in platelet glycoprotein Ibα, Gly to ser at residue 233, in a Japanese family with platelet-type von Willebrand disease

AU - Matsubara, Y.

AU - Murata, Mitsuru

AU - Sugita, K.

AU - Ikeda, Y.

PY - 2003/10

Y1 - 2003/10

N2 - Background: Interaction between platelet glycoprotein (GP)Iba and von Willebrand factor (VWF) has critical roles in both physiological hemostasis and thrombosis. Platelet-type von Willebrand disease (plt-VWD) is a congenital bleeding disorder characterized by gain-of-function mutations of GPIbα. To date, two mutations in GPIbα, G233V and M239V, have been reported in four unrelated families with plt-VWD. Objective: The present study aimed to determine whether G233S of GPIba, a new mutation observed in plt-VWDpa-tients, causes the plt-VWDphenotype and to examine whether conversions to other residues at this position affect VWF binding. Patients and methods: The propositus was a 3-year-old Japanese male. He displayed bleeding symptoms and moderate thrombocytopenia. His brother was similarly affected. Platelets from both patients were analyzed by ristocetin- or shear-induced platelet aggregation. DNA sequencing was performed to analyze the GPIba sequence. We examined the I-labeled VWF binding using a series of recombinant GPIba fragments with different residues at position 233 (G233S, G233A, G233K, and G233D) together with naturally occurring mutations previously reported in patients (G233Vand M239V). Results: Platelet function analysis indicated that platelets from both patients had a typical plt-VWDphenotype. DNA sequen-cing analysis showed a heterozygous mutation of Gly to Ser at residue 233 of GPIba in both patients. The 125I-labeled VWF binding to mutant compared with the wild type displayed three patterns, gain-of-function (G233S, G233V, and M239V), equivalent function (G233A), and loss-of-function (G233K and G233D). Conclusions: The G233S is a molecular basis of plt-VWD, and residue 233 plays critical roles in regulating VWF binding.

AB - Background: Interaction between platelet glycoprotein (GP)Iba and von Willebrand factor (VWF) has critical roles in both physiological hemostasis and thrombosis. Platelet-type von Willebrand disease (plt-VWD) is a congenital bleeding disorder characterized by gain-of-function mutations of GPIbα. To date, two mutations in GPIbα, G233V and M239V, have been reported in four unrelated families with plt-VWD. Objective: The present study aimed to determine whether G233S of GPIba, a new mutation observed in plt-VWDpa-tients, causes the plt-VWDphenotype and to examine whether conversions to other residues at this position affect VWF binding. Patients and methods: The propositus was a 3-year-old Japanese male. He displayed bleeding symptoms and moderate thrombocytopenia. His brother was similarly affected. Platelets from both patients were analyzed by ristocetin- or shear-induced platelet aggregation. DNA sequencing was performed to analyze the GPIba sequence. We examined the I-labeled VWF binding using a series of recombinant GPIba fragments with different residues at position 233 (G233S, G233A, G233K, and G233D) together with naturally occurring mutations previously reported in patients (G233Vand M239V). Results: Platelet function analysis indicated that platelets from both patients had a typical plt-VWDphenotype. DNA sequen-cing analysis showed a heterozygous mutation of Gly to Ser at residue 233 of GPIba in both patients. The 125I-labeled VWF binding to mutant compared with the wild type displayed three patterns, gain-of-function (G233S, G233V, and M239V), equivalent function (G233A), and loss-of-function (G233K and G233D). Conclusions: The G233S is a molecular basis of plt-VWD, and residue 233 plays critical roles in regulating VWF binding.

KW - Glycoprotein iba

KW - Mutagenesis

KW - Platelet-type von willebrand disease

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