Naturally occurring mutations in glycoprotein Ibalpha that result in defective ligand binding and synthesis of a truncated protein. Blood 1998 Jul 01;92(1):175-83
Date
06/25/1998Pubmed ID
9639514DOI
10.1182/blood.v92.1.175.413a36_175_183Scopus ID
2-s2.0-2642625659 (requires institutional sign-in at Scopus site) 47 CitationsAbstract
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): GPIbalpha, GPIbbeta, 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 GPIbalpha 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 GPIbalpha 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 GPIbalpha, inherited from a mutant paternal allele. The Bernard-Soulier phenotype was observed in siblings who were compound heterozygotes for these two mutations. Although GPIbalpha was not detected on the surface of the patient's platelets, soluble GPIbalpha could be immunoprecipitated from plasma. When plasmids encoding GPIbalpha containing the Cys65 --> Arg mutation were transiently transfected into Chinese hamster ovary (CHO) cells stably expressing the GPbeta-IX complex (CHObetaIX), the expression of GPIbalpha was similar to the wild-type (WT) GPIbalpha, but did not bind vWF. When plasmids encoding GPIbalpha containing the Trp498 --> stop were transiently transfected into CHObetaIX, the surface expression of GPIbalpha was barely detectable compared with the WT GPIbalpha. 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.
Author List
Kenny D, Jónsson OG, Morateck PA, Montgomery RRAuthor
Robert R. Montgomery MD Adjunct Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AdultAmino Acid Sequence
Animals
Binding Sites
CHO Cells
Child, Preschool
Cricetinae
Female
Heterozygote
Humans
Ligands
Male
Molecular Sequence Data
Mutation
Platelet Glycoprotein GPIb-IX Complex
Protein Binding
