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Glanzmann's thrombasthenia associated with deletion-insertion and
alternative splicing in the glycoprotein IIb gene
H Peretz, N Rosenberg, S Usher, E Graff, PJ Newman, BS Coller and U Seligsohn
Department of Hematology, Chaim Sheba Medical Center, Tel-Hashomer, Israel.
Glanzmann's thrombasthenia is a bleeding disorder characterized by a
decrease or absence of the functional platelet membrane glycoprotein (GP)
complex, GPIIb/IIIa (alpha IIb beta 3). We describe a new deletion-
insertion mutation in the GPIIb gene causing type I Glanzmann's
thrombasthenia in two siblings of a consanguineous Iranian-Jewish family.
The proband's platelets bound more antibodies against the vitronectin
receptor-alpha V beta 3 than normal platelets, suggesting a normal GPIIIa
(beta 3) gene and a defect in the GPIIb gene. Sequencing of amplified cDNA
and genomic DNA fragments showed a 6-bp deletion and 31-bp insertion in
exon 25 of the GPIIb gene. The predominant platelet GPIIb mRNA of the
proband was a product of the splicing of exon 24 to a cryptic AG acceptor
site in the insertion and encoded for deletion of amino acids Leu817-Asn826
and insertion of eight different amino acids. Cotransfection of COS-7 cells
with expression vectors containing wild- type GPIIIa cDNA and the mutated
GPIIb cDNA failed to produce detectable amounts of GPIIb/IIIa on the
surface of the cells. Allele- specific restriction analysis of genomic DNA
of family members showed homozygosity for the mutation in the affected
siblings, heterozygosity in the parents, and homozygosity for the normal
allele in an unaffected sibling. The observed mutation is in a region that
is conserved from rodents to humans and has been suggested to be involved
in the interaction between GPIIb and GPIIIa when these GPs are complexed in
solution.
Volume 85,
Issue 2,
pp. 414-420,
01/15/1995
Copyright © 1995 by The American Society of Hematology
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