title: Glanzmann thrombasthenia Frankfurt I is associated with a point mutation Thr176Ile in the N-terminal region of alpha IIb subunit integrin.
abstract: 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 alpha IIb beta 3 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 alpha IIb and beta 3 subunits showed a novel point mutation C621T in alpha IIb cDNA, leading to a missense substitution of threonine for isoleucine at position 176. Coexpression of normal beta 3 and mutant alpha IIb(1176) isoform in mammalian cells showed a marked reduction in the expression of alpha IIb beta 3 heterodimer when compared to the wild-type and a decreased intracellular level of alpha IIb. The T176 I mutation is located in the N-terminal region in the W3:1-2 connecting strand of the beta-propeller. These data suggest that the N-terminal alpha IIb domain plays an important structural role in the formation of heterodimer and that it is also involved in fibrinogen binding.
authors.affiliation: Deutsche Klinik für Diagnostik, Aukammallee 33, 65191 Wiesbaden, Germany. westrup.hst@dkd-wiesbaden.de
authors.forename: Dagmar
authors.initials: D
authors.lastname: Westrup
authors.forename: Sentot
authors.initials: S
authors.lastname: Santoso
authors.forename: Katja
authors.initials: K
authors.lastname: Follert-Hagendorff
authors.forename: Steffen
authors.initials: S
authors.lastname: Bassus
authors.forename: Melitta
authors.initials: M
authors.lastname: Just
authors.forename: Bernd
authors.initials: B
authors.lastname: Jablonka
authors.forename: Carl M
authors.initials: CM
authors.lastname: Kirchmaier
mesh_terms: D001780:Blood Coagulation Tests; D004252:DNA Mutational Analysis; D005260:Female; D005340:Fibrinogen / Q000378:metabolism; D006801:Humans; D008875:Middle Aged; D020125:Mutation, Missense; D010973:Platelet Adhesiveness / Q000235:genetics; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000032:analysis; D040201:Platelet Membrane Glycoprotein IIb / Q000032:analysis / Q000235:genetics*; D017354:Point Mutation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000032:analysis; D013915:Thrombasthenia / Q000235:genetics*
chemical_list: D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D040201:Platelet Membrane Glycoprotein IIb; D012333:RNA, Messenger; D005340:Fibrinogen