PROTHROMBIN FRANKFURT - A DYSFUNCTIONAL PROTHROMBIN CHARACTERIZED BY SUBSTITUTION OF GLU-466 BY ALA

We have identified a patient with a dysfunctional prothrombin that we have designated Prothrombin Frankfurt. The proband was characterized b y a prothrombin activity level of 13% and 20% compared to normal contr ols using two different assays with a normal prothrombin antigen level of 91% of normal controls. The generic defect responsible for the abn ormal prothrombin activity was determined by the polymerase chain reac tion followed by single-strand conformation polymorphism (PCR-SSCP) an alysis and by DNA sequence analysis of the human prothrombin gene. Sub stitution of a C for an A at nucleotide 10177 in the human prothrombin gene of the proband was identified, which results in the replacement of Glu-466 by Ala. The proband and one sister were homozygous for this mutation. Both parents, as well as one brother, were found to be hete rozygous for this mutation. The same amino acid substitution was previ ously identified to be responsible for the dysfunctional protein Proth rombin Salakta and was hypothesized to result in altered substrate spe cificity. Four polymorphisms were also identified in the prothrombin g ene from the proband when compared to the published sequence at nucleo tides 554, 4048, 4272 and 10253.