Molecular analysis of a compound heterozygote for hypoprothrombinemia and dysprothrombinemia (-G 7248/7249 and ARG 340 TRP)

Hypoprothrombinemia is an uncommon hereditary coagulation defect characterized by low levels of biologically active prothrombin. Automated fluorescence-based DNA sequence analysis of amplified genomic DNA was used to define prothrombin gene regions from a patient with severe functional hypoprothrombinemia and little detectable prothrombin antigen. Two changes that alter amino acid sequence were observed: a deletion of one nucleotide (- G, 7248/7249) in exon 8 of one allele, causing a frameshift at codon 249/250 that results in premature termination of translation; and a C → T change resulting in the substitution of tryptophan (TGG) for arginine (CGG) at amino acid 340 in exon 10 of the prothrombin gene. Computer modeling of the thrombin molecule confirmed that arginine 340 is located at the surface of the thrombin molecule, which points to the aqueous solvent. As tryptophan is a highly hydrophobic amino acid, the Arg → Trp change may be associated with instability of the thrombin molecule.