GENE-MUTATIONS IN 21 UNRELATED CASES OF PHENOTYPIC HETEROZYGOUS PROTEIN-C DEFICIENCY AND THROMBOSIS

Mutations have been identified in the protein C gene in 21 patients wi th venous thromboembolism and phenotypic heterozygous protein C defici ency. In 20 probands, single mutations were the only abnormalities ide ntified by sequencing all coding regions, intron exon boundaries and t he promoter region back to -1540. In one proband 2 mutations were iden tified and in another family 2 mutations were identified (but not both in the proband). Of the 23 mutations, 18 resulted in predicted amino acid substitutions, 3 were mutations resulting in stop codons, one was a mutation within a consensus splice sequence and another a 9 base pa ir insertion within exon 5 (this region within exon 5 is proposed as a deletion/insertion hat spot). A novel polymorphism was also, uniquely , identified in the propeptide region of the molecule (Pro-21Pro; CCT to CCC) in a kindred from Hong Kong. Cosegregation of the protein C ge ne mutation with protein C deficiency could be determined in 13 famili es. In a further family, phenotypic protein C deficiency and the genet ic mutation cosegregated in only 4/5 members. The first thrombotic inc ident occurred in the probands between the ages of 11 and 59 years and 12 individuals suffered recurrent thrombosis. Thrombosis occurred in at least one other family member in 9/21 families, but in 2 of these i t was inconsistently associated with protein C deficiency. An independ ent genetic risk factor, factor V Arg506Gln (FV Leiden) was identified in 2 probands (and 3 family members) and in 4 protein C deficient mem bers of a third family but not in the proband. The results suggest tha t in the majority of probands with thrombosis and phenotypic protein C deficiency, a single protein C gene mutation is associated with throm bosis. However, it is also possible that additional unknown genetic ri sk factors contribute to the thrombotic risk. An added, acquired, risk factor leads to thrombosis at an early age (<25 years).