Identification of five novel mutations in the factor XI gene (F11) of patients with factor XI deficiency

Quélin, Florence; Mathonnet, Florence; Potentini-Esnault, Catherine; Trigui, Nawel; Peynet, J; Bastenaire, Brigitte; Guillon, Laurent; Bigel, Marie-Laure; Sauger, A.; Mazurier, Claudine; Mazancourt, Philippe de

doi:10.1097/01.mbc.0000198054.50257.96

Cited by 17 publications

(16 citation statements)

References 30 publications

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“…For PCR amplification, oligonucleotide primers amplifying all 15 exons and exon-intron boundaries of the FXI gene and a 641 pb fragment of the promoter region were generated as previously described [14,16]. Amplifications were performed using Perkin-Elmer 2400 or 9600 thermocyclers (Perkin-Elmer, Wellesley, Massachusetts, USA) with PCR conditions as previously described [14,16].…”

Section: Sample Preparation and Coagulation Assaysmentioning

confidence: 99%

Prospective analysis of factor XI deficiencies in the Marseilles area identified four novel mutations among 12 consecutive unrelated families

Quélin

Frère²,

Pouymayou³

et al. 2009

Blood Coagulation &Amp; Fibrinolysis

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Hereditary factor XI (FXI) deficiency is an autosomal bleeding disorder of variable severity but without a clear relationship between bleeding and FXI levels or mutation location or both. In the present study, the molecular basis of FXI deficiency in 16 patients from 12 families originating from the Marseilles area in the south of France was studied. FXI defect was evidenced by routine laboratory tests showing prolonged activated partial thromboplastin times and decreased factor XI activities. The promotor region, exons 1-15, and the exon-intron boundaries of the FXI gene were sequenced. Four novel mutations were found; three were missense mutations (Cys212Ser, Gly350Arg and Thr381Leu resulting from heterozygote mutation in exon 7, 10 and 11, respectively), and one was a one base deletion in exon 4 that induces a frameshift creating a stop codon four residues later (Thr57Ile fsX4). Eight previously reported mutations were also found. Contrarily to the Jewish, Basques or Briton populations, no recurrent mutation was identified. This cohort also illustrates that bleeding events occur not exclusively and not systematically in severe FXI deficiency but also in patients characterized by a mild FXI deficiency.

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Section: Sample Preparation and Coagulation Assaysmentioning

confidence: 99%

Prospective analysis of factor XI deficiencies in the Marseilles area identified four novel mutations among 12 consecutive unrelated families

Quélin

Frère²,

Pouymayou³

et al. 2009

Blood Coagulation &Amp; Fibrinolysis

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“…Seven mutations are novel and four of those are missense mutations (V20A, C58Y, Y427C and C527Y). The four missense mutations and a previously reported uncharacterized missense mutation 19 were expressed in BHK cells and analyzed in order to discern the associated functional defects. Two mutations (V20A and C58Y) are in residues located in FXI apple 1 domain, two are in the catalytic domain (Y427C and C527Y) and the one previously reported (E297K) is in the apple 4 domain.…”

Section: Discussionmentioning

confidence: 99%

“…Of the remaining nine mutations detected in this study (Table 1) and previously reported, 5,18-22 four were missense mutations (F283L, E297K, E323K and C398Y). Three of these four missense mutations have been characterized by expression studies 20,21,23 whereas the fourth, E297K, 19 has not been expressed, and was, therefore, characterized in this study. Its expression in BHK cells revealed impaired secretion (4.5% of WT FXI) despite the presence of 70% of WT FXI antigen in cell lysate, which was shown to be a dimer by western blot analysis ( Figure 2).…”

Section: © F E R R a T A S T O R T I F O U N D A T I O Nmentioning

confidence: 99%

Characterization of seven novel mutations causing factor XI deficiency

Zucker¹,

Zivelin²,

Landau³

et al. 2007

Haematologica

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“…Interestingly, the in silico prediction of the missense variant NM_000128.3: c.943G>A in the F11 locus was not conclusive. According to previously published association data [40], this mutation in heterozygous state is associated with low plasma FXI levels. Thus, it is possible that the in silico predictions could be underestimating its pathogenicity.…”

Section: Discussionmentioning

confidence: 95%

Next generation sequencing to dissect the genetic architecture of KNG1 and F11 loci using factor XI levels as an intermediate phenotype of thrombosis

et al. 2017

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Venous thromboembolism is a complex disease with a high heritability. There are significant associations among Factor XI (FXI) levels and SNPs in the KNG1 and F11 loci. Our aim was to identify the genetic variation of KNG1 and F11 that might account for the variability of FXI levels. The KNG1 and F11 loci were sequenced completely in 110 unrelated individuals from the GAIT-2 (Genetic Analysis of Idiopathic Thrombophilia 2) Project using Next Generation Sequencing on an Illumina MiSeq. The GAIT-2 Project is a study of 935 individuals in 35 extended Spanish families selected through a proband with idiopathic thrombophilia. Among the 110 individuals, a subset of 40 individuals was chosen as a discovery sample for identifying variants. A total of 762 genetic variants were detected. Several significant associations were established among common variants and low-frequency variants sets in KNG1 and F11 with FXI levels using the PLINK and SKAT packages. Among these associations, those of rs710446 and five low-frequency variant sets in KNG1 with FXI level variation were significant after multiple testing correction and permutation. Also, two putative pathogenic mutations related to high and low FXI levels were identified by data filtering and in silico predictions. This study of KNG1 and F11 loci should help to understand the connection between genotypic variation and variation in FXI levels. The functional genetic variants should be useful as markers of thromboembolic risk.

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Identification of five novel mutations in the factor XI gene (F11) of patients with factor XI deficiency

Cited by 17 publications

References 30 publications

Prospective analysis of factor XI deficiencies in the Marseilles area identified four novel mutations among 12 consecutive unrelated families

Prospective analysis of factor XI deficiencies in the Marseilles area identified four novel mutations among 12 consecutive unrelated families

Characterization of seven novel mutations causing factor XI deficiency

Next generation sequencing to dissect the genetic architecture of KNG1 and F11 loci using factor XI levels as an intermediate phenotype of thrombosis

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