Six different point mutations in seven Danish families with symptomatic protein C deficiency.

Six different point mutations of the protein C gene are described in seven Danish families with protein C deficiency associated with an increased risk of venous thromboembolism. All affected family members are heterozygotes for the mutated protein C genotype. One mutation is a G2992-->A transition at position +5 in the 5' splice site of intron D. The other five mutations affect the protein coding region. One is a C1432-->T transition in exon III converting the highly conserved Arg15 to Trp in the Gla-domain. Another mutation is a G3157-->C transversion in exon V converting the non-conserved Gly72 to Arg in the epidermal growth factor domain. The remaining three mutations are located in non-conserved amino acid positions in exon IX and affect the serine proteinase domain. The first is a G8559-->C transversion converting Gly282 to Arg. The second is a C8571-->T transition (present in two families) converting Arg286 to Cys. The third is a C8695-->T transition converting Pro327 to Leu. In each family the protein C deficiency cosegregates or probably cosegregates (one family, G8559-->C) with the mutation. All affected family members exhibit a reduction of both the antigen and the functional plasma concentration of protein C to approximately 50% of normal indicating that the mutated protein C is not present (type 1 deficiency) or only present in low amounts in plasma. Agarose gel electrophoresis followed by Western blotting shows that the Arg15-->Trp substitution is associated with a normal as well as an abnormal migrating plasma protein C band.(ABSTRACT TRUNCATED AT 250 WORDS)