Expanding the Mutation Spectrum Affecting αIIbβ3 Integrin in Glanzmann Thrombasthenia: Screening of the ITGA2B and ITGB3 Genes in a Large International Cohort.
We report the largest international study on Glanzmann thrombasthenia (GT), an inherited bleeding disorder where defects of the ITGA2B and ITGB3 genes cause quantitative or qualitative defects of the αIIbβ3 integrin, a key mediator of platelet aggregation. Sequencing of the coding regions and splice sites of both genes in members of 76 affected families identified 78 genetic variants (55 novel) suspected to cause GT. Four large deletions or duplications were found by quantitative real-time PCR. Families with mutations in either gene were indistinguishable in terms of bleeding severity that varied even among siblings. Families were grouped into type I and the rarer type II or variant forms with residual αIIbβ3 expression. Variant forms helped identify genes encoding proteins mediating integrin activation. Splicing defects and stop codons were common for both ITGA2B and ITGB3 and essentially led to a reduced or absent αIIbβ3 expression; included was a heterozygous c.1440-13_c.1440-1del in intron 14 of ITGA2B causing exon skipping in seven unrelated families. Molecular modeling revealed how many missense mutations induced subtle changes in αIIb and β3 domain structure across both subunits, thereby interfering with integrin maturation and/or function. Our study extends knowledge of GT and the pathophysiology of an integrin.
Institut de Rhythmologie et de Modélisation Cardiaque, Plateforme Technologique d'Innovation Biomédicale, Hôpital Xavier Arnozan, Pessac, France.
Alan T
AT
Nurden
Xavier
X
Pillois
Mathieu
M
Fiore
Marie-Christine
MC
Alessi
Mariana
M
Bonduel
Marie
M
Dreyfus
Jenny
J
Goudemand
Yves
Y
Gruel
Schéhérazade
S
Benabdallah-Guerida
Véronique
V
Latger-Cannard
Claude
C
Négrier
Diane
D
Nugent
Roseline D
RD
Oiron
Margaret L
ML
Rand
Pierre
P
Sié
Marc
M
Trossaert
Lorenzo
L
Alberio
Nathalie
N
Martins
Peggy
P
Sirvain-Trukniewicz
Arnaud
A
Couloux
Mathias
M
Canault
Juan Pablo
JP
Fronthroth
Mathilde
M
Fretigny
Paquita
P
Nurden
Roland
R
Heilig
Christine
C
Vinciguerra
D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005091:Exons; D015321:Gene Rearrangement; D056726:Genetic Association Studies; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D039421:Integrin alpha2 / Q000737:chemistry / Q000235:genetics; D039661:Integrin beta3 / Q000737:chemistry / Q000235:genetics; D008958:Models, Molecular; D009154:Mutation; D010641:Phenotype; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000737:chemistry / Q000235:genetics*; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D022821:RNA Splice Sites; D012326:RNA Splicing; D017384:Sequence Deletion; D013915:Thrombasthenia / Q000175:diagnosis / Q000235:genetics*
C056564:ITGA2B protein, human; C061248:ITGB3 protein, human; D039421:Integrin alpha2; D039661:Integrin beta3; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D022821:RNA Splice Sites
Glanzmann thrombasthenia; ITGA2B; ITGB3; integrin αIIbβ3; molecular modeling