Spectrum of factor XI (F11) mutations in the UK population – 116 index cases and 140 mutations

Mitchell, Michael J.; Mountford, Roger; Butler, Rachel; Alhaq, Anwar; Dai, Letian; Savidge, Geoffrey F.; Bolton‐Maggs, Paula

doi:10.1002/humu.9439

Cited by 47 publications

(56 citation statements)

References 29 publications

(37 reference statements)

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“…Consequently, the C58Y substitution disrupting the C58-C28 appeared to be responsible for the totally impaired secretion despite the presence of FXI in lysed cells. Two other substitutions of C58 were recently reported by Mitchell et al 18 One, a C58F substitution, was detected in a homozygous patient whose FXI activity was <1% of normal, and the second, a C58R substitution, was identified in a heterozygous patient whose FXI activity was 42%. Other disulfide bond disruptions by mutations in cysteine residues were reported in apple 1 (C38R) and apple 3 (C237Y) 7 with both displaying, similarly to C58Y, intact FXI production but impaired secretion.…”

Section: Discussionmentioning

confidence: 65%

Characterization of seven novel mutations causing factor XI deficiency

Zucker¹,

Zivelin²,

Landau³

et al. 2007

Haematologica

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Section: Discussionmentioning

confidence: 65%

Characterization of seven novel mutations causing factor XI deficiency

Zucker¹,

Zivelin²,

Landau³

et al. 2007

Haematologica

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“…A total of 10 different mutations, four being novel, were identified in 10 families, confirming the genetic heterogeneity of the disease. Of these 10 mutations, three nonsense, two splice site mutations and one missense mutation have previously been described [15][16][17][18][19][20][21][22][23]. The p. Glu135 Ã (type II) mutation was identified in five individuals from two unrelated families with no known Jewish ancestry.…”

Section: Discussionmentioning

confidence: 97%

Molecular basis and bleeding manifestations of factor XI deficiency in 11 Turkish families

Keskin¹,

Gürsel

Kaya

et al. 2015

Blood Coagulation &Amp; Fibrinolysis

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Factor XI (FXI) deficiency is an autosomal bleeding disorder characterized by variable bleeding tendency. In the present study, the gene encoding FXI (F11) was analyzed by direct sequencing in 33 individuals belonging to 11 unrelated Turkish families, and the bleeding tendency was quantitatively assessed by means of a bleeding questionnaire in 27 individuals with low FXI clotting activity and/or mutated F11 gene. We identified 10 distinct mutations (five missense, three nonsense and two splice site), four of which were novel. No mutation was found in one family. Of the four novel mutations, homozygosity for a c.89T>C (p.Phe30Ser) mutation and compound heterozygosity for a c.646G>A (p.Asp216Asn) mutation with the known c.403G>T (p.Glu135) type II Jewish mutation were associated with severe deficiency, whilst heterozygosity for the novel c.1655A>C (p.His552Arg) and c.1627G>A (p.Glu543Lys) mutations was associated with partial deficiency. p.Glu135 was found in 19% (5/27) of the mutated alleles. Bleeding score was positive in 57% (4/7) of individuals with severe and 39% (7/18) of those with partial deficiency. It was significantly correlated with clinical severity of bleeding (r = 0.43, P = 0.02), but not with FXI clotting activity (P > 0.05). There was no optimal cut-off level of the bleeding score that could predict FXI deficiency. We conclude that the spectrum of mutations found in this study reflects the genetic heterogeneity of FXI deficiency in the Turkish population. Quantitative assessment of the bleeding symptoms by a bleeding questionnaire seems to be useful for evaluating the severity of bleeding episodes, but it can not be recommended as a screening tool for FXI deficiency.

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“…Hereditary FXI deficiency (OMIM 264900) is an autosomal bleeding disorder of variable severity. It is most commonly found in individuals of Ashkenazi Jewish ancestry [2] and sporadically found in other populations [3,4].…”

Section: Introductionmentioning

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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Spectrum of factor XI (F11) mutations in the UK population – 116 index cases and 140 mutations

Cited by 47 publications

References 29 publications

Characterization of seven novel mutations causing factor XI deficiency

Characterization of seven novel mutations causing factor XI deficiency

Molecular basis and bleeding manifestations of factor XI deficiency in 11 Turkish families

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

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