Gly319 → Arg substitution in the dysfunctional prothrombin Segovia

The molecular defect of a congenitally dysfunctional form of prothrombin, prothrombin Segovia, was identified in a patient with a severe bleeding tendency, reduced prothrombin coagulant activity, and normal antigen level. Nucleotide sequencing of amplified DNA revealed a G-A change at nucleotide 7539 of exon 9 of the prothrombin gene. This resulted in the substitution of Gly 319 by Arg, The proband was homozygous for this mutation, his father and brother were heterozygous. Mle surmised that the substitution, which occurs near the site of cleavage of prothrombin by factor Xa (Arg320-Ile321), altered the conformation of the protein making the cleavage site inaccessible.