Thirty-three Novel Mutations in the Protein C Gene

Summary

We analyzed the protein C gene (PROC) with the denaturing gradient gel electrophoresis (DGGE) scanning strategy in a series of 129 patients with suspected protein C (PC) deficiency (93 with low plasma PC levels and 36 with borderline level). At least one sequence variation was found in 104 of the 129 patients. Thirty-nine sequence variations (found in 72 patients) were already reported detrimental mutations. Thirty-three were novel sequence variations, of which 19 (found in 25 patients) were probably detrimental. Five novel mutations (A1T, R9H, S11R, S12R and K193Q) were associated with qualitative plasma PC deficiency, suggesting or confirming the functional importance of amino acids at these positions. This strategy confirmed the diagnosis of inherited PC deficiency in 79/93 (84.9%) patients with low plasma PC levels and 14/36 (38.8%) patients with borderline values. In order to explain abnormal PC levels observed in patients who did not carry detrimental mutations, screening for the -1654C/T and -1641A/G PROC promoter polymorphisms known to influence plasma PC concentrations was performed. The frequency of the CG allele associated with lower PC concentrations was slightly but not significantly lower in 82 heterozygotes for detrimental PROC gene mutations than in 36 patients with no identified detrimental mutations.

Keywords

Protein C - thrombosis - coagulation - gene

^* J.F. Abgrall (Hôpital Augustin Morvan, Brest, France), M.F. Aillaud and I. Juhan-Vague (CHU Timone, Marseille, France), N. Ajzenberg and M. Dreyfus (Hôpital Bicêtre, Le Kremlin-Bicêtre, France), M. Berruyer and M.C. Trzeciak (Hôpital Edouard Herriot, Lyon, France), C. Boinot (CHU La Miletrie, Poitiers, France), F. Bridey and D. de Prost (Hôpital Bichat, Paris, France), S. Brun (Hôpital Gaston Douvergne, Nîmes, France), M. David (Hôpital Ste-Justine, Montréal, Canada), E. de Maistre and T. Lecompte (CHU de Nancy, France), P. de Moerloose and G. Reber (Hôpital Cantonal Universitaire, Geneva, Switzerland), M.H. Denninger (Hôpital Beaujon, Clichy, France), E. Dupuy (Hôpital Lariboisière, Paris, France), J. Emmerich, J.N. Fiessinger, A. Jaque, A. Rance, M.E. Sirieix and J.F. Vitoux (Hôpital Broussais, Paris, France), M. Gouault-Heilmann (Hôpital Henri Mondor, Créteil, France), B. Jude (Hôpital Cardiologique, Lille, France), A. Le Querrec (CHU de la Côte de Nacre, Caen, France), M. Mexme (Orléans, France), A. Michaud-Mallet (Institut Arnault Tzanck, St-Laurent du Var, France), U. Nowak Gottl (Westfälische Wilhems Universität, Münster, Germany), P. Priollet (Hôpital St-Joseph, Paris, France), J. Reynaud (Hôpital Nord, Saint-Etienne, France), V. Siguret (Hôpital Charles Foix, Ivry, France), B. Tardy (Hôpital Bellevue, Saint-Etienne, France), P. Toulon (Hôpital Cochin, Paris, France), N.H. Toumi (Hôpital d’Enfants, Tunis, Tunisie), F. Truchaud (Institut de Biologie des Hôpitaux, Nantes, France), C. Vergnes (Hôpital Cardiologique du Haut-Lévêque, Pessac, France), M. Wolf (Hôpital Antoine Béclère, Clamart, France).

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