Glanzmann thrombasthenia Frankfurt I is associated with a point mutation Thr176Ile in the N-terminal region of alpha IIb subunit integrin.
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.
Westrup
Dagmar
D
Deutsche Klinik für Diagnostik, Aukammallee 33, 65191 Wiesbaden, Germany. westrup.hst@dkd-wiesbaden.de
Santoso
Sentot
S
Follert-Hagendorff
Katja
K
Bassus
Steffen
S
Just
Melitta
M
Jablonka
Bernd
B
Kirchmaier
Carl M
CM
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*
D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D040201:Platelet Membrane Glycoprotein IIb; D012333:RNA, Messenger; D005340:Fibrinogen