Nonsense Mutation in the Glycoprotein IBα Coding Sequence Associated with Bernard-Soulier Syndrome

• Published in: Proceedings of the National Academy of Sciences - PNAS 1990-03, Vol.87 (5), p.2026-2030
• Main Authors: Ware, Jerry, Russell, Susan R., Vicente Vicente, Scharf, Rudiger E., Tomer, Aaron, McMIllan, Robert, Ruggeri, Zaverio M.
• Format: Article
• Language: English
• Subjects: 550201 - Biochemistry- Tracer Techniques; ADHESION; Adult; Alleles; ANIMALS; AUTORADIOGRAPHY; Base Sequence; BASIC BIOLOGICAL SCIENCES; Bernard Soulier syndrome; Bernard-Soulier Syndrome - blood; Bernard-Soulier Syndrome - genetics; BIOLOGICAL MATERIALS; BLOOD; BLOOD CELLS; Blood Platelet Disorders - genetics; BLOOD PLATELETS; BODY FLUIDS; Children; CONGENITAL DISEASES; DISEASES; DNA; DNA - blood; DNA - genetics; DNA - isolation & purification; DNA BASE TRANSITIONS; DNA SEQUENCING; Female; GENE MUTATIONS; General practice; genes; GLYCOPROTEINS; HEMORRHAGE; HEREDITARY DISEASES; Humans; Immunoblotting; Male; MAMMALS; MAN; MATERIALS; Medical genetics; MEMBRANE PROTEINS; Molecular Sequence Data; Mutation; MUTATIONS; Nonsense mutation; Oligonucleotide Probes; ORGANIC COMPOUNDS; PATHOGENESIS; PATHOLOGICAL CHANGES; Pedigree; Platelet Membrane Glycoproteins - genetics; Platelets; Polymerase Chain Reaction; PRIMATES; PROTEINS; RECEPTORS; Restriction Mapping; STRUCTURAL CHEMICAL ANALYSIS; SYMPTOMS; VERTEBRATES
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.87.5.2026

Three distinct gene products, the α and β chains of glycoprotein (GP) Ib and GP IX, constitute the platelet membrane GP Ib-IX complex, a receptor for von Willebrand factor and thrombin involved in platelet adhesion and aggregation. Defective function of the GP Ib-IX complex is the hallmark of a rare congenital bleeding disorder of still undefined pathogenesis, the Bernard-Soulier syndrome. We have analyzed the molecular basis of this disease in one patient in whom immunoblotting of solubilized platelets demonstrated absence of normal GP Ibα but presence of a smaller immunoreactive species. The truncated polypeptide was also present, along with normal protein, in platelets from the patient's mother and two of his four children. Genetic characterization identified a nucleotide transition changing the Trp-343 codon (TGG) to a nonsense codon (TGA). Such a mutation explains the origin of the smaller GP Ibα, which by lacking half of the sequence on the carboxyl-terminal side, including the transmembrane domain, cannot be properly inserted in the platelet membrane. Both normal and mutant codons were found in the patient, suggesting that he is a compound heterozygote with a still unidentified defect in the other GP Ibα allele. Nonsense mutation and truncated GP Ibα polypeptide were found to cosegregate in four individuals through three generations and were associated with either Bernard-Soulier syndrome or carrier state phenotype. The molecular abnormality demonstrated in this family provides evidence that defective synthesis of GP Ibα alters the membrane expression of the GP Ib-IX complex and may be responsible for Bernard-Soulier syndrome.