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Blood, Vol. 93 No. 9 (May 1), 1999:
pp. 2968-2975
The Critical Interaction of Glycoprotein (GP) Ib With GPIX A
Genetic Cause of Bernard-Soulier Syndrome
Dermot Kenny,
Patricia A. Morateck,
Joan C. Gill, and
Robert R. Montgomery
From the Blood Research Institute, the Blood Center of Southeastern
Wisconsin, and the Departments of Medicine, Pediatrics, and Pathology,
Medical College of Wisconsin, Milwaukee, WI.
Bernard-Soulier syndrome is an uncommon bleeding disorder caused by
a quantitative or qualitative defect in the platelet glycoprotein (GP)Ib/IX complex. The complex is composed of four subunits, GPIb , GPIb , GPIX, and GPV. Here we describe the molecular basis of a novel
Bernard-Soulier syndrome variant in a patient in whom GPIb and GPIX
were undetectable on the platelet surface. DNA sequence analysis showed
normal sequence for GPIb, GPIX, and GPV. The GPIb gene has been
mapped to the 22q11.2 region of chromosome 22 which was deleted from
one chromosome of this patient. There was a single nucleotide deletion
within the codon for Ala 80 in GPIb within the other allele. This
mutation causes a translational frame shift that encodes for 86 altered
amino acids and predicts a premature stop 15 amino acids short of the
length of the wild-type protein. Transient coexpression of the mutant
GPIb in 293T cells with wild-type GPIb and GPIX resulted in the
surface expression of GPIb, but the absence of GPIX. Moreover, when
a plasmid encoding the wild-type GPIb was transiently transfected
into Chinese hamster ovary cells stably expressing GP, which retain
the capacity to reexpress GPIX, there was a significant increase in the
surface expression of GPIX. In contrast, when the mutant GPIb was
transiently transfected into these cells, GPIX was not reexpressed on
the plasma surface. Thus, a deletion of one copy of GPIb and a
single nucleotide deletion in the codon for Ala 80 within the remaining GPIb allele causes the Bernard-Soulier phenotype through an
interaction of GPIb with GPIX resulting in the absence of GPIb on
the plasma membrane. The interaction of GPIb with GPIX is essential
for the functional expression of GPIb.
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