Glanzmann thrombasthenia Frankfurt I is associated with a point mutation Thr176Ile in the N-terminal region of αIIb subunit integrin

Dagmar Westrup; Sentot Santoso; Katja Follert-Hagendorff; Steffen Bassus; Melitta Just; Bernd Jablonka; Carl M. Kirchmaier

doi:10.1160/TH04-03-0170

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2004; 92(05): 1040-1051
DOI: 10.1160/TH04-03-0170

Platelets and Blood Cells

Schattauer GmbH

Glanzmann thrombasthenia Frankfurt I is associated with a point mutation Thr176Ile in the N-terminal region of αIIb subunit integrin

Dagmar Westrup

¹Deutsche Klinik für Diagnostik, Wiesbaden, Germany

,

Sentot Santoso

²Institute for Clinical Immunology and Transfusion Medicine, Justus Liebig University, Giessen, Germany

,

Katja Follert-Hagendorff

¹Deutsche Klinik für Diagnostik, Wiesbaden, Germany

,

Steffen Bassus

¹Deutsche Klinik für Diagnostik, Wiesbaden, Germany

,

Melitta Just

³Aventis, Frankfurt-Hoechst, Germany

,

Bernd Jablonka

³Aventis, Frankfurt-Hoechst, Germany

,

Carl M. Kirchmaier

¹Deutsche Klinik für Diagnostik, Wiesbaden, Germany

› Author Affiliations

Abstract

Summary

In this study, we report on the characterization of a patient with Glanzmann thrombasthenia (GT). Immunochemical analysis on platelets from the patient showed that the expression of αIIbβ3 was only 25% of that in normal healthy controls, suggesting a case of GT. Functional analysis revealed a total lack of fibrinogen binding capacity. Molecular genetic analysis of the full-length cDNA sequences of αIIb and β3 subunits showed a novel point mutation C621T in αIIb cDNA, leading to a missense substitution of threonine for isoleucine at position 176. Coexpression of normal β3 and mutant αIIb^I176 isoform in mammalian cells showed a marked reduction in the expression of αIIbβ3 heterodimer when compared to the wild-type and a decreased intracellular level of αIIb. The T176 I mutation is located in the N-terminal region in the W3:1-2 connecting strand of the β-propeller. These data suggest that the N-terminal αIIb domain plays an important structural role in the formation of heterodimer and that it is also involved in fibrinogen binding.

Keywords

Bleeding disorder - platelet - integrin - β-propeller

Full Text

References

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