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

Abstract

SummaryIn 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 αIIbI176 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.