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Recurrence of a Phe31Ser mutation in the Gla domain of blood coagulation factor X, in unrelated Algerian families: a founder effect?
Author(s) -
Akhavan Sepideh,
Chafa Ouerdia,
Nsoure Obame Fatou,
Torchet MarieFrançoise,
Reghis Abderrezak,
Fischer AnneMarie,
TaponBretaudière Jacqueline
Publication year - 2007
Publication title -
european journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.904
H-Index - 84
eISSN - 1600-0609
pISSN - 0902-4441
DOI - 10.1111/j.1600-0609.2007.00836.x
Subject(s) - missense mutation , haplotype , mutation , exon , allele , mutant , microbiology and biotechnology , population , biology , heterozygote advantage , genetics , antigen , coagulation , medicine , gene , environmental health
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.