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Naturally Occurring Mutations in Glycoprotein Ib That Result in
Defective Ligand Binding and Synthesis of a Truncated Protein
Dermot Kenny,
Ólafur G. Jónsson,
Patricia A. Morateck, and
Robert R. Montgomery
From the Departments of Medicine, Pediatrics, and Pathology, Medical
College of Wisconsin, Milwaukee; The Blood Research Institute, the
Blood Center of Southeastern Wisconsin, Milwaukee; and the Department
of Pediatrics, Reykjavík Hospital, Iceland.
The platelet GPIb-V-IX complex is the receptor for the initial
binding of von Willebrand factor (vWF) mediating platelet adhesion. The
complex is composed of four membrane-spanning glycoproteins (GP):
GPIb , GPIb , GPIX, and GPV. Bernard-Soulier syndrome results from
a qualitative or quantitative defect in one or more components of the
platelet membrane GPIb-V-IX complex. We describe the molecular basis of
a novel Bernard-Soulier syndrome variant in two siblings in whom
GPIb was not detected on the platelet surface but that was present
in a soluble form in plasma. DNA sequence analysis showed that the
affected individuals were compound heterozygotes for two mutations.
One, inherited from a maternal allele, a T777  C point
mutation in GPIb converting Cys65 Arg within the
second leucine rich repeat, the other, a single nucleotide substitution
(G2078 A) for the tryptophan codon (TGG) causing a
nonsense codon (TGA) at residue 498 within the transmembrane region of
GPIb, inherited from a mutant paternal allele. The Bernard-Soulier
phenotype was observed in siblings who were compound heterozygotes for
these two mutations. Although GPIb was not detected on the
surface of the patient's platelets, soluble GPIb could be
immunoprecipitated from plasma. When plasmids encoding GPIb
containing the Cys65 Arg mutation were transiently
transfected into Chinese hamster ovary (CHO) cells stably expressing
the GP-IX complex (CHOIX), the expression of GPIb was similar
to the wild-type (WT) GPIb, but did not bind vWF. When plasmids
encoding GPIb containing the Trp498 stop were
transiently transfected into CHOIX, the surface expression of
GPIb was barely detectable compared with the WT GPIb. Thus, this
newly described compound heterozygous defect produces Bernard-Soulier
syndrome by a combination of synthesis of a nonfunctional protein and
of a truncated protein that fails to insert into the platelet membrane
and is found circulating in plasma.
Blood, Vol. 92 No. 1 (July 1), 1998:
pp. 175-183
© 1998 by The American Society of Hematology.
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