Molecular genetic analysis of severe protein C deficiency

Severe protein C deficiency is a rare, early onset, venous thrombotic condi tion that is inherited as an autosomal recessive trait. The protein C (PROC ) genes of nine unrelated individuals with severe protein C deficiency were sequenced yielding a total of 13 different lesions. Eight of these were no vel, including a gross gene deletion. three missense mutations, two micro-d eletions, a splicing mutation and a single base-pair substitution in the HN F-3 binding sire in the PROC gene promoter. Evidence for the pathogenicity of the mutations detected was obtained by molecular modelling, in vitro spl icing assay and reporter gene assay. Neither the plasma protein C activity level nor the nature of the PROC gene lesions detected were found to be a g ood prognostic indicator of the age of onset or clinical severity of thromb otic symptoms. Other factors may thus complicate the relationship between g enotype and clinical phenotype, indeed, in two patients, the inheritance of either one or two Factor V Leiden alleles in addition to two PROC gene les ions could have served to precipitate the thrombotic events. No association was however apparent between clinical severity and the possession of a par ticular promoter polymorphism genotype. Despite the absence of a clear geno type-phenotype relationship, the molecular genetic analysis of the severe r ecessive form of protein C deficiency potentiates both the counselling of a ffected families and the prevision of antenatal exclusion diagnosis.