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Blood, Vol. 93 No. 3 (February 1), 1999:
pp. 866-875
Molecular Genetic Analysis of a Compound Heterozygote for the
Glycoprotein (GP) IIb Gene Associated With Glanzmann's Thrombasthenia:
Disruption of the 674-687 Disulfide Bridge in GPIIb Prevents
Surface Exposure of GPIIb-IIIa Complexes
Consuelo González-Manchón,
Marta Fernández-Pinel,
Elena G. Arias-Salgado,
Milagros Ferrer,
M.-Victoria Alvarez,
Soledad García-Muñoz,
Matilde S. Ayuso, and
Roberto Parrilla
From the Department of Pathophysiology and Human Molecular Genetics,
Centro de Investigaciones Biológicas (CSIC), Madrid, Spain; the
Unidad de Biofísica, Instituto de Química
Física (CSIC), Madrid, Spain; and the Laboratory of Analytical
Hematology, University Hospital "La Paz," Madrid, Spain.
This work was aimed at elucidating the molecular genetic lesion(s)
responsible for the thrombasthenic phenotype of a patient whose low
platelet content of glycoprotein (GP) IIb-IIIa indicated that it was a
case of type II Glanzmann's thrombasthenia (GT). The parents did not
admit consanguinity and showed a reduced platelet content of
GPIIb-IIIa. Polymerase chain reaction (PCR)-single-stranded conformational polymorphism analysis of genomic DNA showed
no mutations in the patient's GPIIIa and two novel mutations in the GPIIb gene: one of them was a heterozygous splice junction mutation, a
C A transversion, at position +2 of the exon 5-intron 5 boundary [IVS5(+2)CA] inherited from the father. The
predicted effect of this mutation, insertion of intron 5 (76 bp) into
the GPIIb-mRNA, was confirmed by reverse transcription-PCR
analysis of platelet mRNA. The almost complete absence of this mutated
form of GPIIb-mRNA suggests that it is very unstable. Virtually all of
the proband's GPIIb-mRNA was accounted for by the allele inherited
from the mother showing a T2113C transition that
changes Cys674Arg674 disrupting the
674-687 intramolecular disulfide bridge. The proband showed a platelet
accumulation of proGPIIb and minute amounts of GPIIb and GPIIIa.
Moreover, transfection and immunoprecipitation analysis demonstrated
that [Arg674]GPIIb is capable of forming a heterodimer
complex with GPIIIa, but the rate of subunit maturation and the surface
exposure of GPIIb-IIIa are strongly reduced. Thus, the intramolecular
674-687 disulfide bridge in GPIIb is essential for the normal
processing of GPIIb-IIIa complexes. The additive effect of these two
GPIIb mutations provides the molecular basis for the thrombasthenic phenotype of the proband.
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