Evidence of a founder effect for the protein C gene 3363 inserted C mutation in thrombophilic pedigrees of French origin

We have previously reported that the 3363 inserted (Ins) C mutation in exon 6 of the protein C gene was pre-sent in four unrelated French patients and in four French Canadian families with type I protein C deficiency as well as in a large Vermont protein C deficient kindred of French Canadian origin . The present study was designed to investigate the likelihood of the exist ence of a founder effect for this mutation in protein C deficient individua ls of French origin living in France.. Quebec and Vermont. In order to demo nstrate a possible founder effect for the 3363 InsC mutation, we have previ ously constructed a high-resolution genetic map to locate several highly po lymorphic markers close to the protein C locus. Thereafter, the markers D2S 347, D2S2339, D2S383, D2S2271 and D2S2215 were genotyped in 117 heterozygot es from France (n = 7), Quebec (n = 36) or Vermont (n = 74). The allelic fr equency distribution of these five markers was also determined in fifty con trol French Canadian subjects and thirty-two unaffected members of the Verm ont kindred with normal protein C levels and compared with their frequency in our cohort of heterozygotes. Our data suggest that patients from Quebec and Vermont carry a common haplotype at the protein C locus. Moreover, in o rder to study the evolutionary history of the 3363 InsC mutation, we traced back the ascending genealogy of one proband in each of the families with t his mutation. These results showed that the 3363 InsC mutation was most pro bably introduced in North America by a couple of French settlers who establ ished themselves in 1669 on Isle d'Orleans located near Quebec City. All he terozygotes for the 3363 InsC mutation living in North America are related to these founders within 10 generations. Thus, these families afford a uniq ue opportunity to evaluate the role of the protein C system in thrombophili a due to the high degree of linkage disequilibrium at the protein C gene, w hich in essence holds that variable more constant than in a more heterogene ous population.