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Thromb Haemost 2001; 86(04): 1000-1006
DOI: 10.1055/s-0037-1616524
Special Article
Schattauer GmbH

Evidence of a Founder Effect for the Protein C Gene 3363 Inserted C Mutation in Thrombophilic Pedigrees of French Origin

Patrick Couture
1   Department of Internal Medicine, CHUL Research Center, CHUQ, Québec, Canada
,
Edwin G. Bovill
2   Departments of Pathology and Biochemistry, University of Vermont, Burlington, USA
,
Christine Demers
4   Laboratory of Hereditary Cancers, CHUL Research Center, CHUQ, Québec, Canada
,
Robert Delage
3   Department of Hematology, Hôpital du Saint-Sacrement, CHA, Québec, Canada
,
Bruce T. Scott
2   Departments of Pathology and Biochemistry, University of Vermont, Burlington, USA
,
Julia E. Valliere
2   Departments of Pathology and Biochemistry, University of Vermont, Burlington, USA
,
Peter W. Callas
2   Departments of Pathology and Biochemistry, University of Vermont, Burlington, USA
,
Michèle Jomphe
5   BALZAC Project, University du Québec, Chicoutimi, Canada
,
Frits R. Rosendaal
6   Departments of Clinical Epidemiology and Hematology, Leiden University Medical Center, Leiden, The Netherlands
,
Martine Aiach
7   Laboratory of Hemostasis, Broussais Hospital, Paris, France
,
George L. Long
2   Departments of Pathology and Biochemistry, University of Vermont, Burlington, USA
› Author Affiliations
Further Information

Publication History

Received 12 January 2001

Accepted after revision 16 May 2001

Publication Date:
09 December 2017 (online)

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Summary

We have previously reported that the 3363 inserted (Ins) C mutation in exon 6 of the protein C gene was present 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 existence of a founder effect for this mutation in protein C deficient individuals of French origin living in France, Québec and Vermont. In order to demonstrate a possible founder effect for the 3363 InsC mutation, we have previously constructed a high-resolution genetic map to locate several highly polymorphic markers close to the protein C locus. Thereafter, the markers D2S347, D2S2339, D2S383, D2S2271 and D2S2215 were genotyped in 117 heterozygotes from France (n = 7), Québec (n = 36) or Vermont (n = 74). The allelic frequency distribution of these five markers was also determined in fifty control French Canadian subjects and thirty-two unaffected members of the Vermont kindred with normal protein C levels and compared with their frequency in our cohort of heterozygotes. Our data suggest that patients from Québec and Vermont carry a common haplotype at the protein C locus. Moreover, in order 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 this mutation. These results showed that the 3363 InsC mutation was most probably introduced in North America by a couple of French settlers who established themselves in 1669 on Isle d‘Orleans located near Québec City. All heterozygotes for the 3363 InsC mutation living in North America are related to these founders within 10 generations. Thus, these families afford a unique opportunity to evaluate the role of the protein C system in thrombophilia due to the high degree of linkage disequilibrium at the protein C gene, which in essence holds that variable more constant than in a more heterogeneous population.

Keywords

Protein C deficiency - thrombophilia - genetics
 

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