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

Patrick Couture; Edwin G. Bovill; Christine Demers; Robert Delage; Bruce T. Scott; Julia E. Valliere; Peter W. Callas; Michèle Jomphe; Frits R. Rosendaal; Martine Aiach; George L. Long

doi:10.1055/s-0037-1616524

Thrombosis and Haemostasis, Table of Contents

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

¹Department of Internal Medicine, CHUL Research Center, CHUQ, Québec, Canada

,

Edwin G. Bovill

²Departments of Pathology and Biochemistry, University of Vermont, Burlington, USA

,

Christine Demers

⁴Laboratory of Hereditary Cancers, CHUL Research Center, CHUQ, Québec, Canada

,

Robert Delage

³Department of Hematology, Hôpital du Saint-Sacrement, CHA, Québec, Canada

,

Bruce T. Scott

²Departments of Pathology and Biochemistry, University of Vermont, Burlington, USA

,

Julia E. Valliere

²Departments of Pathology and Biochemistry, University of Vermont, Burlington, USA

,

Peter W. Callas

²Departments of Pathology and Biochemistry, University of Vermont, Burlington, USA

,

Michèle Jomphe

⁵BALZAC Project, University du Québec, Chicoutimi, Canada

,

Frits R. Rosendaal

⁶Departments of Clinical Epidemiology and Hematology, Leiden University Medical Center, Leiden, The Netherlands

,

Martine Aiach

⁷Laboratory of Hemostasis, Broussais Hospital, Paris, France

,

George L. Long

²Departments of Pathology and Biochemistry, University of Vermont, Burlington, USA

› Author Affiliations

Abstract

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

Full Text

References

References
1 Esmon C. Protein-C: biochemistry, physiology, and clinical implications. Blood 1983; 62: 1155-8.
2 Marlar R, Kleiss A, Griffin J. Mechanism of action of human activated protein C, a thrombin-dependent anticoagulant enzyme. Blood 1982; 59: 1067-72.
3 Rocchi M, Roncuzzi L, Santamaria R, Archidiacono N, Dente L, Romeo G. Mapping through somatic cell hybrids and cDNA probes of protein C to chromosome 2, factor X to chromosome 13, and alpha 1-acid glycoprotein to chromosome 9. Hum Genet 1986; 74: 30-3.
4 Kato A, Miura O, Sumi Y, Aoki N. Assignment of the human protein C gene (PROC) to chromosome region 2q14-q21 by in situ hybridization. Cytogenet Cell Genet 1988; 47: 46-7.
5 Patracchini P, Aiello V, Palazzi P, Calzolari E, Bernardi F. Sublocalization of the human protein C gene on chromosome 2q13-q14. Hum Genet 1989; 81: 191-2.
6 Koeleman BP, Reitsma PH, Bakker E, Bertina RM. Location on the human genetic linkage map of 26 genes involved in blood coagulation. Thromb Haemost 1997; 77: 873-8.
7 Cox S, Bryant SP, Collins A, Weissenbach J, Donis-Keller H, Koeleman BP, Steinkasserer A, Spurr NK. Integrated genetic map of human chromosome 2. Ann Hum Genet 1995; 59: 413-34.
8 Couture P, Demers C, Morissette J, Delage R, Jomphe M, Couture L, Simard J. 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. Thromb Haemost 1998; 80: 551-6.
9 Foster DC, Yoshitake S, Davie EW. The nucleotide sequence of the gene for human protein C. Proc Natl Acad Sci U S A 1985; 82: 4673-7.
10 Plutzky J, Hoskins JA, Long GL, Crabtree GR. Evolution and organization of the human protein C gene. Proc Natl Acad Sci USA 1986; 83: 546-50.
11 Reitsma PH, Bernardi F, Doig RG, Gandrille S, Greengard JS, Ireland H, Krawczak M, Lind B, Long GL, Poort SR, Saito H, Sala N, Witt I, Cooper DN. Protein C deficiency: a database of mutations, 1995 update. On behalf of the Subcommittee on Plasma Coagulation Inhibitors of the Scientific and Standardization Committee of the ISTH. Thromb Haemost 1995; 73: 876-89.
12 Allaart CF, Poort SR, Rosendaal FR, Reitsma PH, Bertina RM, Briet E. Increased risk of venous thrombosis in carriers of hereditary protein C deficiency defect. Lancet 1993; 341: 134-8.
13 Miletich J, Sherman L, Broze GJ. Absence of thrombosis in subjects with heterozygous protein C deficiency. N Engl J Med 1987; 317: 991-6.
14 Tait RC, Walker ID, Reitsma PH, Islam SI, McCall F, Poort SR, Conkie JA, Bertina RM. Prevalence of protein C deficiency in the healthy population. Thromb Haemost 1995; 73: 87-93.
15 Gladson CL, Scharrer I, Hach V, Beck KH, Griffin JH. The frequency of type I heterozygous protein S and protein C deficiency in 141 unrelated young patients with venous thrombosis. Thromb Haemost 1988; 59: 18-22.
16 Broekmans AW, Van der Linden IK, Veltkamp JJ, Bertina RM. Prevalence of isolated protein C deficiency in patients with venous thromboembolic disease and in the population. Thromb Haemost 1983; 50: 350a.
17 Marlar RA, Montgomery RR, Broekmans AW. Report on the diagnosis and treatment of homozygous protein C deficiency. Report of the Working Party on Homozygous Protein C Deficiency of the ICTH-Subcommittee on Protein C and Protein S. Thromb Haemost 1989; 61: 529-31.
18 Gandrille S, Aiach M. Identification of mutations in 90 of 121 consecutive symptomatic French patients with a type I protein C deficiency. The French INSERM Network on Molecular Abnormalities Responsible for Protein C and Protein S deficiencies. Blood 1995; 86: 2598-605.
19 Tomczak JA, Ando RA, Sobel HG, Bovill EG, Long GL. Genetic analysis of a large kindred exhibiting type I protein C deficiency and associated thrombosis. Thromb Res 1994; 74: 243-54.
20 Bouchard G. Current issues and new prospects for computerized record linkage in the province of Québec. Historical Methods 1992; 25: 67-73.
21 Bouchard G, Roy R, Casgrain B, Hubert M. Computer in human sciences: from family reconstitution to population reconstruction. In: From information to knowledge: conceptual and content analysis by computer. Nissan E, Schmidt KM. eds. Intellect: Oxford, UK; 1995: 201-7.
22 Jomphe M, Casgrain B. Base de données généalogiques RETRO: structure des données. Document Balzac IC-181, Chicoutimi (Québec) Canada: 2000
23 Jomphe M, Casgrain B, Vézina H. Analyses généalogiques à partir du fichier RETRO. Document Balzac IC-204, Chicoutimi (Québec) Canada: 2000
24 Heyer E, Tremblay M. Variability of the genetic contribution of Québec population founders associated to some deleterious genes. Am J Hum Genet 1995; 56: 970-8.
25 Bovill EG, Bauer KA, Dickerman JD, Callas P, West B. The clinical spectrum of heterozygous protein C deficiency in a large New England kindred. Blood 1989; 73: 712-7.
26 Mayr E. Animal species and evolution. Cambridge, MA: Harvard University Press; 1963
27 Reitsma PH, Poort SR, Allaart CF, Briet E, Bertina RM. The spectrum of genetic defects in a panel of 40 Dutch families with symptomatic protein C deficiency type I: heterogeneity and founder effects. Blood 1991; 78: 890-4.
28 Levo A, Kuismanen K, Holopainen P, Vahtera E, Rasi V, Krusius T, Partanen J. Single founder mutation (W380G) in type II protein C deficiency in Finland. Thromb Haemost 2000; 84: 424-8.
29 Charbonneau H, Desjardins B, Guillemette A, Landry Y, Légaré J, Nault F. Naissance d‘une population. Les Français établis au Canada au XVIIe siècle. Montréal: Les Presses de l‘Université de Montréal; 1987
30 Bouchard G, De Braekeleer M. Histoire d’un génôme. Population et génétique dans l‘est du Québec. Sillery, Québec: Presses de l‘Université du Québec; 1991
31 Lavoie Y. L’émigration des Québécois aux États-Unis, de 1840 à 1930. Québec: Éditeur Officiel: 1979
32 Davignon J, Roy M. Familial hypercholesterolemia in French-Canadians: taking advantage of the presence of a “founder effect”. Am J Cardiol 1993; 72: 6D-10D.
33 Couture P, Morissette J, Gaudet D, Vohl MC, Gagné C, Bergeron J, Després JP, Simard J. Fine mapping of low-density lipoprotein receptor gene by genetic linkage on chromosome 19p13.1-p13.3 and study of the founder effect of four French Canadian low-density lipoprotein receptor gene mutations. Atherosclerosis 1999; 143: 145-51.
34 Gaudet D, Vohl MC, Couture P, Moorjani S, Tremblay G, Perron P, Gagné C, Després JP. Contribution of receptor negative versus receptor defective mutations in the LDL-receptor gene to angiographically assessed coronary artery disease among young (25-49 years) versus middle-aged (50-64 years) men. Atherosclerosis 1999; 143: 153-61.
35 John SW, Rozen R, Laframboise R, Laberge C, Scriver CR. Five mutations at the PAH locus account for almost 90% of PKU mutations in French-Canadians from eastern Quebec. Hum Mutat 1992; 1: 72-4.
36 De Braekeleer M, Dionne C, Gagné C, Julien P, Brun D, Ven MM, Lupien PJ. Founder effect in familial hyperchylomicronemia among French Canadians of Québec. Hum Hered 1991; 41: 168-73.