Nonsense mutation in the glycoprotein Ib. alpha. coding sequence associated with Bernard-Soulier syndrome

Journal Article · Thu Mar 01 00:00:00 EST 1990 · Proceedings of the National Academy of Sciences of the United States of America; (USA)

DOI:https://doi.org/10.1073/pnas.87.5.2026· OSTI ID:5989485

Ware, J; Russell, S R; Vicente, V; Scharf, R E; Tomer, A; McMillian, R; Ruggeri, Z M ^[1]

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1. Research Institute of Scripps, La Jolla, CA (USA)

Three distinct gene products, the {alpha} and {beta} 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. The authors have analyzed the molecular basis of the disease in one patient in whom immunoblotting of solubilized platelets demonstrated absence of normal GP Ib{alpha} 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 Ib{alpha}, 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 Ib{alpha} allele. Nonsense mutation and truncated GP Ib{alpha} 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 Ib{alpha} alters the membrane expression of the GP Ib-IX complex and may be responsible for Bernard-Soulier syndrome.

• OSTI ID: 5989485
• Journal Information: Proceedings of the National Academy of Sciences of the United States of America; (USA), Vol. 87:5; ISSN 0027-8424
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
GENE MUTATIONS
DNA SEQUENCING
GLYCOPROTEINS
AUTORADIOGRAPHY
HEREDITARY DISEASES
PATHOGENESIS
ADHESION
BLOOD PLATELETS
CONGENITAL DISEASES
DNA BASE TRANSITIONS
HEMORRHAGE
MAN
RECEPTORS
ANIMALS
BIOLOGICAL MATERIALS
BLOOD
BLOOD CELLS
BODY FLUIDS
DISEASES
MAMMALS
MATERIALS
MEMBRANE PROTEINS
MUTATIONS
ORGANIC COMPOUNDS
PATHOLOGICAL CHANGES
PRIMATES
PROTEINS
STRUCTURAL CHEMICAL ANALYSIS
SYMPTOMS
VERTEBRATES
550201* - Biochemistry- Tracer Techniques