Faculty Collaboration Database

The critical interaction of glycoprotein (GP) IBbeta with GPIX-a genetic cause of Bernard-Soulier syndrome. Blood 1999 May 01;93(9):2968-75

Date

04/27/1999

Pubmed ID

10216092

DOI

10.1182/blood.v93.9.2968

Scopus ID

2-s2.0-0033135652 (requires institutional sign-in at Scopus site)   63 Citations

Abstract

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, GPIbalpha, GPIbbeta, GPIX, and GPV. Here we describe the molecular basis of a novel Bernard-Soulier syndrome variant in a patient in whom GPIbalpha and GPIX were undetectable on the platelet surface. DNA sequence analysis showed normal sequence for GPIbalpha, GPIX, and GPV. The GPIbbeta 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 GPIbbeta 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 GPIbbeta in 293T cells with wild-type GPIbalpha and GPIX resulted in the surface expression of GPIbalpha, but the absence of GPIX. Moreover, when a plasmid encoding the wild-type GPIbbeta was transiently transfected into Chinese hamster ovary cells stably expressing GPalpha, which retain the capacity to reexpress GPIX, there was a significant increase in the surface expression of GPIX. In contrast, when the mutant GPIbbeta was transiently transfected into these cells, GPIX was not reexpressed on the plasma surface. Thus, a deletion of one copy of GPIbbeta and a single nucleotide deletion in the codon for Ala 80 within the remaining GPIbbeta allele causes the Bernard-Soulier phenotype through an interaction of GPIbbeta with GPIX resulting in the absence of GPIbalpha on the plasma membrane. The interaction of GPIbbeta with GPIX is essential for the functional expression of GPIbalpha.

Author List

Kenny D, Morateck PA, Gill JC, Montgomery RR

Author

Robert R. Montgomery MD Adjunct Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adolescent
Alanine
Amino Acid Sequence
Animals
Base Sequence
Bernard-Soulier Syndrome
CHO Cells
Chromosome Mapping
Chromosomes, Human, Pair 22
Codon
Codon, Terminator
Cricetinae
Frameshift Mutation
Gene Deletion
Humans
Male
Platelet Glycoprotein GPIb-IX Complex
Recombinant Proteins
Sequence Deletion
Transfection