A common ancestral mutation (C128X) occurring in 11 non‐Jewish families from the UK with factor XI deficiency

Abstract

mutation (C128X) occurring in 11 non-Jewish families from the UK with factor XI deficiency. J Thromb Haemost 2004; 2: 918-24. Summary. Factor XI (FXI) deficiency is a mild bleeding disorder that is particularly common in Ashkenazi Jews, but has been reported in all populations. In Jews, two FXI gene (F11) mutations (a stop codon in exon 5, E117X, type II, and a point mutation in exon 9, F283L, type III) are particularly common, but in other populations a variety of different mutations have been described. In the Basque region of France one mutation, C38R in exon 3, was found in eight of 12 families studied, haplotype analysis suggesting a founder effect. In the course of screening 78 unrelated individuals (including 15 Jewish and 12 Asian) we have found 10 Caucasian non-Jewish patients with the mutation C128X in exon 5. Individuals were investigated because of a personal or family history of bleeding, or finding a prolonged activated partial thromboplastin time. Individuals negative for the type II and type III mutations were screened by a combination of SSCP and heteroduplex analysis. The C128X mutation was found in 10 families (one previously described). Among three individuals with severe FXI deficiency, one was homozygous for the C128X mutation, and two were compound heterozygotes for the C128X and another mutation; other individuals were carriers of the C128X mutation. This is a nonsense mutation producing a truncated protein; individuals have FXI antigen levels concordant with FXI coagulant activity. Haplotype analysis of 11 families, including a further kindred previously reported from the USA, but which originally came from the UK (in which the index patient was homozygous for C128X), suggests a founder effect.

Factor XI gene mutations in factor XI deficient patients of the Czech Republic

“…Our results confirm that the molecular basis of this disorder is largely heterogeneous outside the Jewish population [11][12][13]26].…”

“…Although the Type II mutation is also frequent among Iraqi Jews and Palestinian Arabs [9], Phe283Leu is almost unique in Ashkenazi Jews, but it can be rarely observed in other populations [10]. More than 150 FXI gene mutations have been so far reported (see http://www.med.unc.edu/isth/mutationsdatabases/FactorXI_2007.htlm, http://www.wienkav.at/kav/kar/ texte_anzeigen.asp?ID57137, and http://www.factorxi.com), and a founder effect has been demonstrated in a few populations in whom prevalent ancestral mutations were found (Cys38Arg in French Basques, Gln88X in French patients from Nantes, and Cys128X in English patients) [11][12][13].…”

Simultaneous genotyping of coagulation factor XI type II and type III mutations by multiplex real-time polymerase chain reaction to determine their prevalence in healthy and factor XI-deficient Italians

“…18 Haplotype analyses confirmed that the frequency of these mutations is due to founder effects. In particular, the C128X mutation is found in 2% of individuals screened for hemochromatosis in the UK, 18 and in 2% of normal individuals from the north-west of England, suggesting that severe FXI deficiency in the UK may be more common than previously thought. 19 The frequency of the C128X mutation is similar to that of the C38R mutation, which is present in 1% of French Basques.…”

Characterization of seven novel mutations causing factor XI deficiency

“…4 Two less common mutations were described in Jews: type I, a splice-site mutation and type IV, a 14bp deletion between exon 14 and intron N. 5,6 Other relatively frequent mutations, C38R and C128X, were reported in French Basques and Britons, respectively. [7][8][9] More than 120 other sporadic mutations have been identified in different populations [http://www.med.unc.edu/isth, http://www.factorXI.org]. 10 Characterization of the growing number of FXI mutations has shed light on the relationship between structure and function of this protein, and has contributed to defining the importance of its various domains.…”