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αIIbβ3 integrin: new allelic variants in Glanzmann thrombasthenia, effects on ITGA2B and ITGB3 mRNA splicing, expression, and structure–function
Author(s) -
Jallu Vincent,
Dusseaux Mathilde,
Panzer Simon,
Torchet MarieFrançoise,
Hezard Nathalie,
Goudemand Jenny,
de Brevern Alexandre G.,
Kaplan Cécile
Publication year - 2010
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.21179
Subject(s) - biology , missense mutation , exon , rna splicing , genetics , microbiology and biotechnology , allele , mutation , intron , mutant , gene , alternative splicing , rna
Glanzmann thrombasthenia (GT) is an autosomal recessive inherited bleeding disorder characterized by an impaired platelet aggregation due to defects in integrin αIIbβ3 ( ITGA2B , ITGB3 ), a fibrinogen receptor. Mutations from 24 GT patients and two carriers of various origins, Caucasian, North‐African and Asian were characterized. Promoter and exon sequences of αIIb and β3 genes were amplified and directly sequenced. Among 29 identified mutations, 17 new allelic variants resulting from nonsense, missense and deletion/insertion mutations were described. RNA alterations were evaluated by using Web servers. The αIIb p.S926L, p.V903F, and β3 p.C38Y, p.M118R, p.G221D substitutions prevented complex expression at the surface of COS‐7 cells by altering the αIIb or the β3 subunit structure. As shown by free energy analyses applied on the resolved structure of αIIbβ3 and structural modeling of the mutant, the p.K253M substitution of β3 helped to define a key role of the K253 in the interaction of the αIIb β‐propeller and the β3 β‐I domains. finally, the αIIb p.Q595H substitution allowed cell surface expression of the complex but its corresponding c.2800G>T mutation is predicted to alter normal RNA splicing. In conclusion, our study yielded the discovery of 17 new GT allelic variants, revealed the key role of K253 of αIIb for the αIIbβ3 complex formation and provides an additional example of an apparently missense mutation causing a splicing defect. Hum Mutat 30:1–10, 2010. © 2010 Wiley‐Liss, Inc.