TYPE-I PROTEIN-C DEFICIENCY IN FRENCH-CANADIANS - EVIDENCE OF A FOUNDER EFFECT AND ASSOCIATION OF SPECIFIC PROTEIN-C GENE-MUTATIONS WITH PLASMA-PROTEIN-C LEVELS

Protein C (PROC) deficiency is one of the most common autosomal codomi nant diseases. Although more than 150 germline mutations in the PROC g ene have been described around the world, the spectrum of mutations am ong French Canadians is unknown. We have identified one frameshift (33 63 ins C) and two missense mutations (R178Q and T298M) in 7 French Can adian families with type I PROC deficiency. In order to demonstrate a possible founder effect for the 3363 ins C mutation, we have construct ed a high-resolution genetic map to locate several highly polymorphic markers close to PROC locus. We have then genotyped five markers in 36 heterozygotes for the 3363 ins C mutation. Our data suggest that thes e patients carry a common haplotype at the PROC locus. Immunologic pla sma PROC levels of heterozygotes and genetically normal relatives were also correlated with the nature of the mutation in the coding sequenc e and with the genotype of three polymorphisms in the PROC promoter. W e found that the mean immunologic plasma PROC levels were lower in het erozygotes for the frameshift mutation 3363 ins C compared to heterozy gotes for one of the two missense mutations R178Q and T298M (0.46 vs 0 .61; P = 0.0004). Moreover, this difference cannot be explained by the genetic variation of the three polymorphisms in the PROC promoter whi ch accounts for only 10.4% of the variation of immunologic PROC levels in non-deficient subjects. These results suggest that the nature of t he mutation in the coding sequence of PROC gene may modulate immunolog ic plasma PROC levels.