title: Recurrence of a Phe31Ser mutation in the Gla domain of blood coagulation factor X, in unrelated Algerian families: a founder effect?
abstract: The presence of gene lesions in blood coagulation factor X (FX) was investigated in eight FX-deficient patients with severe bleeding symptoms, originating from five unrelated Algerian families (FX coagulant activity <1%, FX antigen ranging from 2% to 16%). A missense mutation (p.Phe31Ser) in the Gla domain was found in homozygous form for all patients but one, who is a compound heterozygote for the Phe31Ser mutation and for a non-sense mutation, Tyr130Term in EGF-2 domain. The haplotypes of FX alleles were determined by the following allelic variants located in the promoter: g.1323_1330delTTGTGA (A1/A2), g.1449T>C, g.1451C>A, upstream to exon 3: g.17257C>T and downstream to exon 3: g.17396A>C. The A1-C-A-T-C haplotype was found on each allele bearing the Phe31Ser mutation in the eight FX deficient patients contrasting with its low frequency (8%) in a control Algerian population (in which the Phe31Ser substitution was absent). The patients came from the same geographical area of Algeria (5/8 are certainly from Kabyle origin) and the haplotype analysis suggests a founder effect. Transient expression study reveals that, for the mutant FX-Phe31Ser, FX antigen level was 60% in conditioned media and 140% in cell lysates compared with the wild type FX. The partial retention and intracellular accumulation of the mutant FX might be due to impaired folding and/or conformational changes, and the discrepancies observed between the FX antigen level in COS-7 cell supernatant (60%) and in the patients plasma (2-16%) to an in vivo increased clearance of the secreted unstable FX mutant.
authors: INSERM, U765, Paris, France.
authors: Sepideh
authors: S
authors: Akhavan
authors: Ouerdia
authors: O
authors: Chafa
authors: Fatou Nsoure
authors: FN
authors: Obame
authors: Marie-Françoise
authors: MF
authors: Torchet
authors: Abderrezak
authors: A
authors: Reghis
authors: Anne-Marie
authors: AM
authors: Fischer
authors: Jacqueline
authors: J
authors: Tapon-Bretaudière
mesh_terms: D000462:Algeria; D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D002522:Chlorocebus aethiops; D017931:DNA Primers; D005170:Factor X / Q000235:genetics*; D018703:Founder Effect; D006239:Haplotypes; D006801:Humans; D009154:Mutation; D010649:Phenylalanine / Q000235:genetics*; D012694:Serine / Q000235:genetics*
chemical_list: D017931:DNA Primers; D012694:Serine; D010649:Phenylalanine; D005170:Factor X