MOLECULAR ANALYSIS OF A COMPOUND HETERO ZYGOTE FOR HYPOPROTHROMBINEMIA AND DYSPROTHROMBINEMIA (-G 7248 7249 AND ARG-340 TRP)/

Hypoprothrombinemia is an uncommon hereditary coagulation defect chara cterized by low levels of biologically active prothrombin. Automated f luorescence-based DNA sequence analysis of amplified genomic DNA was u sed to define prothrombin gene regions from a patient with severe func tional hypoprothrombinemia and little detectable prothrombin antigen. Two changes that alter amino acid sequence were observed: a deletion o f one nucleotide (-G, 7248/7249) in exon 8 of one allele, causing a fr ameshift at codon 249/250 that results in premature termination of tra nslation; and a C --> T change resulting in the substitution of trypto phan (TGG) for arginine (CGG) at amino acid 340 in exon 10 of the prot hrombin gene. Computer modeling of the thrombin molecule confirmed tha t arginine 340 is located at the surface of the thrombin molecule, whi ch points to the aqueous solvent. As tryptophan is a highly hydrophobi c amino acid, the Arg --> Trp change may be associated with instabilit y of the thrombin molecule.