MOLECULAR CHARACTERIZATION OF A TYPE-I QUANTITATIVE FACTOR-V DEFICIENCY IN A THROMBOSIS PATIENT THAT IS PSEUDO HOMOZYGOUS FOR ACTIVATED PROTEIN-C RESISTANCE

Resistance to activated protein C (APC), which is associated with the FV Leiden mutation in the large majority of the cases, is the most com mon genetic risk factor for thrombosis. Several laboratory tests have been developed to detect the APC-resistance phenotype. The result of t he APC-resistance test (APC-sensitivity ratio, APC-SR) usually correla tes well with the FV Leiden genotype, but recently some discrepancies have been reported. Some thrombosis patients that are heterozygous for FV Leiden show an APC-SR usually found only in homozygotes for the de fect. Some of those patients proved to be compound heterozygotes for t he FV Leiden mutation and for a type I quantitative factor V deficienc y. We have investigated a thrombosis patient characterized by an APC-S R that would predict homozygosity for FV Leiden. DNA analysis showed t hat he was heterozygous for the mutation. Sequencing analysis of genom ic DNA revealed that the patient also is heterozygous for a G(5509)--> A substitution in exon 16 of the factor V gene. This mutation interfer es with the correct splicing of intron 16 and leads to the presence of a null allele, which corresponds to the ''non-FV Leiden'' allele. The conjunction of these two defects in the patient apparently leads to t he same phenotype as observed in homozygotes for the FV Leiden mutatio n.