Molecular Genetic Analysis of Factor XI Deficiency: Identification of Five Novel Gene Alterations and the Origin of Type II Mutation in Portuguese Families

Abstract

SummaryCoagulation factor XI (FXI) deficiency is an inherited autosomal recessive mild bleeding disorder. In this study, we report the molecular genetic analysis of FXI deficiency in six unrelated families of Portuguese origin. The Jewish type II mutation was found in two families, of seemingly Portuguese origin. Haplotype analysis in these families demonstrated that this mutation is of Jewish origin. In the remaining families, five novel FXI mutations have been identified. Two of these mutations (FXI IVS K -10T→A and FXI 1026G→T, cd 324) affect the FXI pre-mRNA splicing. A further two (FXI 307 ins AAGCAAT, cd 85 and FXI 1072 del A, cd 340) introduce frameshifts leading to premature termination codons. The FXI splicing mutation, 1026G→T cd 324, was found in compound heterozygosity with missense mutation FXI K518N. Analysis of the FXI mRNA from the latter genotype demonstrated new donor splice site usage. All reported mutations most likely result in functional null-alleles. In addition, three novel polymorphisms have been identified: at nt -138 in intron A, at codon D125 in exon 5 and at codon T249 in exon 8.

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

“…Given that none of the analyzed individuals reported a Jewish ancestry, we hypothesize that gene flow was responsible for the diffusion of these mutations among Italians as already proposed for other European populations. 21,22 Moreover, gene flow was previously suggested by Peretz and colleagues 14 to explain the transfer of the type II mutation from Middle Eastern Jews to Palestinian Arabs after the settlement of Arabs in Israel in the seventh century after Christ.…”

“…19 The frequency of the C128X mutation is similar to that of the C38R mutation, which is present in 1% of French Basques. 17,20 The type II mutation has been reported in non-Jewish individuals from England, 21 Portugal, 22 and Italy; 23 in all cases haplotype analysis indicated the Jewish origin of the mutation.…”

Factor XI deficiency in French Basques is caused predominantly by an ancestral Cys38Arg mutation in the factor XI gene

“…15 So far, 26 mutations causing factor XI deficiency have been reported. 18,19 Of these, 4 are nonsense mutations, 5 are splice-site mutations, 3 are small insertion/deletion mutations, and the remaining 14 are missense mutations. Six of the missense mutations were localized to the apple 4 domain, and expression of 5 of them revealed impaired secretion of factor XI from transfected cells.…”

Two factor XI mutations in a Chinese family with factor XI deficiency

“…Accordingly, most of the mutations in the factor XI gene have been described in this population [2]. A smaller number of factor XI gene mutations have also been described in other Caucasian [3], English [4], Portuguese [5], Japanese [6,7], and more recently, the French Basque [8] populations. We describe the first reported factor XI gene mutations in a Chinese family.…”