Summary

Protein C (PROC) deficiency is one of the most common autosomalcodominant diseases. Although more than 150 germline mutations inthe PROC gene have been described around the world, the spectrum ofmutations among French Canadians is unknown. We have identifiedone frameshift (3363 ins C) and two missense mutations (R178Q andT298M) in 7 French Canadian families with type I PROC deficiency. Inorder to demonstrate a possible founder effect for the 3363 ins C mutation,we have constructed a high-resolution genetic map to locateseveral highly polymorphic markers close to PROC locus. We havethen genotyped five markers in 36 heterozygotes for the 3363 ins C mutation.Our data suggest that these patients carry a common haplotype atthe PROC locus. Immunologic plasma PROC levels of heterozygotesand genetically normal relatives were also correlated with the nature ofthe mutation in the coding sequence and with the genotype of threepolymorphisms in the PROC promoter. We found that the mean immunologicplasma PROC levels were lower in heterozygotes for theframeshift mutation 3363 ins C compared to heterozygotes for one ofthe two missense mutations R178Q and T298M (0.46 vs 0.61;P = 0.0004). Moreover, this difference cannot be explained by thegenetic variation of the three polymorphisms in the PROC promoterwhich accounts for only 10.4% of the variation of immunologic PROClevels in non-deficient subjects. These results suggest that the nature ofthe mutation in the coding sequence of PROC gene may modulateimmunologic plasma PROC levels.