title: Molecular basis for protein S hereditary deficiency: genetic defects observed in 118 patients with type I and type IIa deficiencies. The French Network on Molecular Abnormalities Responsible for Protein C and Protein S Deficiencies.
abstract: Circulating protein S (PS) is partly bound to C4b-binding protein, and only free PS can act as a cofactor for protein C (PC), a natural anticoagulant. Two types of PS deficiencies are commonly observed in patients with unexplained thrombosis, and they are characterized by having both a low total PS level and a low free PS level (type I) or by having only a low free PS level (type IIa). To elucidate the genetic mechanisms responsible for these two plasma phenotypes, we screened 118 symptomatic patients with type I or type IIa PS deficiency for a PS gene coding sequence variation. A total of 34 mutations, 17 of which were novel, were identified in 65 propositi (70% in type I and 44% in type IIa). In type I deficiency, 29 different mutations were distributed throughout the coding sequence. In type IIa deficiency, five different missense mutations were clustered in exons XII and XIII, with a Ser 460 to Pro mutation accounting for most cases (82%). This points to a role of the domain encoded by exons XII and XIII in the distribution between bound and free PS. The Ser 460 to Pro mutation was associated with the factor V Arg 506 to Gin mutation or a PC gene mutation in about half the patients, suggesting a cooperative effect on clinical expression.
authors.affiliation: Unité INSERM U 428, UFR des Sciences Pharmaceutiques et Biologiques, Paris, France.
authors.forename: D
authors.initials: D
authors.lastname: Borgel
authors.forename: J
authors.initials: J
authors.lastname: Duchemin
authors.forename: M
authors.initials: M
authors.lastname: Alhenc-Gelas
authors.forename: C
authors.initials: C
authors.lastname: Matheron
authors.forename: M
authors.initials: M
authors.lastname: Aiach
authors.forename: S
authors.initials: S
authors.lastname: Gandrille
mesh_terms: D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D015321:Gene Rearrangement / Q000235:genetics; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D017293:Protein S / Q000235:genetics*; D018455:Protein S Deficiency / Q000235:genetics*; D013927:Thrombosis / Q000209:etiology*
chemical_list: D017293:Protein S