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Missense mutations of the glycoprotein (GP) Ib beta gene impairing the GPIb
alpha/beta disulfide linkage in a family with giant platelet disorder
S Kunishima, JA Lopez, S Kobayashi, N Imai, T Kamiya, H Saito and T Naoe
Department of Medicine, Nagoya University Branch Hospital, Higashi-ku,
Japan.
We describe here the molecular basis of an isolated hereditary giant
platelet disorder (GPD) which is not accompanied with thrombocytopenia or
leukocyte inclusion. Platelet aggregation with ristocetin and botrocetin
was almost normal in this patient. Flow cytometric analysis showed that the
glycoprotein (GP) Ib/IX complex was expressed on the platelet membranes at
decreased levels. The amount of platelet GPIb alpha and the plasma
glycocalicin concentration, the water-soluble extracellular portion of GPIb
alpha, were also decreased. The anti-GPIb alpha antibody coprecipitated
GPIb beta and GPIX, although the ratios of these polypeptides to GPIb alpha
was greatly decreased compared with the ratio in normal platelets.
Immunoblot analysis under nonreduced conditions showed that most of the
GPIb alpha in the patient's platelets was not disulfide linked with GPIb
beta. DNA sequencing analysis showed compound heterozygosity for two
independent single nucleotide substitutions: from Tyr (TAC) to Cys (TGC) at
residue 88, and from Ala (GCC) to Pro (CCC) at residue 108 in her GPIb beta
gene. These substitutions were not found in genomic DNA samples from 108
normal individuals. These mutations might result in decreased expression of
the GPIb/IX complex and may influence the association of the complex with
the membrane skeleton, consequently impairing normal platelet morphology.
Furthermore, the phenotype caused by mutations in the subunits of the
GPIb/IX complex could span the spectrum from a normal phenotype, to
isolated GPD, to a full-blown bleeding disorder, such as Bernard-Soulier
syndrome.
Volume 89,
Issue 7,
pp. 2404-2412,
04/01/1997
Copyright © 1997 by The American Society of Hematology
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