Factor XI deficiency in Southern Iran: identification of a novel missense mutation

Factor XI (FXI)-deficiency is a rare coagulation disorder inherited as an autosomal recessive trait, which is most common in Ashkenazi Jews, but also found in other groups like Moslems. We have reviewed for the first time cases of FXI deficiency in southern Iran in order to analyze their mutations related to factor XI, the main clinical and biological features, levels of circulating factor XI, and bleeding history. All 15 exons and exon–intron boundaries of F11 were polymerase chain reaction amplified using sets of primers designed on the basis of the known genomic sequence of the gene. Among bleeding disorder cases, five were FXI-deficient. FXI clotting activity ranged 0.39–16%. All were severely deficient. In all analyzed patients, functional level of FXI was markedly reduced, confirming the diagnosis of quantitative FXI deficiency. Sequencing of F11 identified three mutations: (1) a highly prevalent type II nonsense mutation (Glu117stop) in a homozygous patient, (2) a previously reported missense (Glu547Lys), and (3) novel missense (Gly372Ala) mutation. No causative mutation was found in the sequenced regions of other patients. One novel mutation and two previously described mutations were identified in patients living in southern Iran. No recurrent mutation was found, perhaps because there is a more intense population mixing in southern Iran. Screening a higher number of FXI-deficient patients will also be necessary to reveal the existence of a founder effect for these mutations in the Iranian population.     

One of the two common mutations causing factor XI deficiency in Ashkenazi Jews (type II) is also prevalent in Iraqi Jews, who represent the ancient gene pool of Jews [see comments]

In recent years four mutations causing factor XI deficiency have been identified in Jews of Ashkenazi (European) origin. Two of them, type II (a nonsense mutation) and type III (a missense mutation), were found to prevail among 125 unrelated Ashkenazi Jews with severe factor XI deficiency. A finding of type II mutation in four unrelated Iraqi- Jewish families raised the possibility that this mutation is also common in Iraqi Jews, who represent the ancient gene pool of the Jews. A molecular-based analysis performed in 1,040 consecutively hospitalized patients disclosed the following results: Among 531 Ashkenazi-Jewish patients, the type II allele frequency was 0.0217 and among 509 Iraqi-Jewish patients, 0.0167 (P = .50). The type III allele frequency in the Ashkenazi-Jewish patients was 0.0254, whereas none of 502 Iraqi-Jewish patients examined had this mutation. These data suggest that the type II mutation was present in Jews already 2.5 millenia ago. The data also indicate that the estimated risk for severe factor XI deficiency in Ashkenazi Jews (due to either genotype) is 0.22% and in Iraqi Jews, 0.03%, and that the estimated risk of heterozygosity in Ashkenazi Jews is 9.0% and in Iraqi Jews, 3.3%. As patients with severe factor XI deficiency are prone to bleeding after injury and patients with partial deficiency may have similar bleeding complications when an additional hemostatic derangement is present, the observed high frequencies should be borne in mind when surgery is planned for individuals belonging to these populations.     

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

Factor XI (FXI) deficiency is an autosomal inherited coagulation disorder characterized by bleeding symptoms mainly associated with injury or surgery. Although most of the FXI gene mutations in Ashkenazi Jews are represented by the Glu117stop or Phe283Leu mutations, considerable genetic heterogeneity has been reported in other populations. We report here the genotypic characterization of four families with severe inherited FXI deficiency from the Czech Republic. Seven different gene mutations (three novel) were identified, thus, excluding the existence of a major founder effect in this population. Interestingly, both Glu117stop and Phe283Leu were detected once, further demonstrating the occurrence of these mutations also outside the Jewish populations. In conclusion, we confirm that FXI deficiency in non-Jewish populations is because of different gene mutations; however, the presence of the Glu117stop and Phe283Leu mutations suggests that genetic testing in FXI-deficient patients can start with these two point mutations.     

Severe factor XI deficiency in a Korean woman with a novel missense mutation (Val498Met) and duplication G mutation in exon 13 of the F11 gene

Hereditary factor XI (FXI) deficiency is a rare bleeding disorder inherited in an autosomal recessive manner. The genetic background of FXI deficiency is the mutations in the F11 gene on the chromosome band 4q35. The prevalence is known to be particularly high in Ashkenazi Jews with well documented recurrent mutations; however, founder mutations in F11 have also been reported in non-Jewish patients. In this report, we describe a Korean patient with severe FXI deficiency whose causative mutations were identified by molecular genetic tests. The patient was a 33-year-old pregnant woman. Routine gynecologic workup revealed prolonged activated partial thromboplastin time. Her FXI level was severely decreased at 1% (reference range, 60-140%). Direct sequencing analysis of the F11 gene was performed to identify the causative mutations. The patient was shown to have two different mutations, c.1546 G>A (Val498Met) and c.1560dupG (Tyr503ValfsX32) in the F11 gene. Val498Met is a novel missense mutation, and the Tyr503ValfsX32 mutation was recently reported in a Japanese patient. Both mutations occurred in the exon 13 of F11 and were believed to disrupt the catalytic domain of the FXI protein, leading to severe FXI deficiency. To the best of our knowledge, this is the first genetically confirmed case of severe FXI deficiency in Korea, and more cases are needed to find any signature of founder effect in the Korean population and its potential relationship with other Asian populations.     

Factor XI (plasma thromboplastin antecedent) deficiency in Ashkenazi Jews is a bleeding disorder that can result from three types of point mutations.

Factor XI (plasma thromboplastin antecedent) deficiency is a blood coagulation abnormality occurring in high frequency in Ashkenazi Jews. Three independent point mutations that result in a blood coagulation abnormality have been identified in the factor XI gene of six unrelated Ashkenazi patients. These mutations either disrupt normal mRNA splicing (type I), cause premature polypeptide termination (type II), or result in a specific amino acid substitution (type III). The three different genotypes were present in the six patients as type I/II, type II/III, and type III/III. Thus far no correlation was found between the three genotypes and the bleeding tendency in these patients.     

Factor XI deficiency and its management

Factor XI deficiency has a more variable bleeding tendency than haemophilia A or B. Individuals with severe deficiency have only a mild bleeding tendency, which is typically provoked by surgery, but the risk of bleeding is not restricted to individuals with severe deficiency. The bleeding tendency varies between individuals with similar factor XI levels, and sometimes the bleeding tendency of an individual may vary. The reasons for this are not fully understood, although in cases of severe deficiency there is some correlation between phenotype and genotype.
Factor XI is activated by thrombin. The role of factor XI in physiological processes has become clearer since this fact was discovered, and the discovery has contributed to a revised model of blood coagulation. Factor XI deficiency occurs in all racial groups, but is particularly common in Ashkenazi Jews. The factor XI gene is 23 kilobases long. Two mutations are responsible for most factor XI deficiency in the Ashkenazi population, but a number of other mutations have now been reported in other racial groups.
Individuals with factor XI deficiency may need specific therapy for surgery, accidents, and dental extractions. Several therapies are available which include fresh frozen plasma, factor XI concentrates, fibrin glue, antifibrinolytic drugs, and desmopressin. Each has advantages and risks to be considered. Factor XI concentrate may be indicated for procedures with a significant risk of bleeding especially in younger patients with severe deficiency, but its use in older patients has been associated with thrombotic phenomena. If fresh frozen plasma is to be used it is preferable to obtain one of the virally inactivated products. Fibrin glue is a useful treatment which deserves further study.     

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

Factor XI (FXI) deficiency is an inherited autosomal recessive disorder associated with bleeding of variable severity. However, many cases of dominant disease transmission have been recently described. This disorder is rare in the general population, whereas it is commonly found in individuals of Ashkenazi Jewish ancestry. This study reports the molecular genetic analysis of FXI deficiencies in 11 unrelated families of different origin. Five novel mutations have been identified. Severe FXI deficiency of two unrelated patients resulted from two novel mutations: one deletion (960-961delGT) in exon 9 predicting a frameshift, and a Ser-4Leu mutation located in the signal peptide. In addition, three novel missense mutations associated with partial FXI deficiency have been identified: Cys122Tyr, Glu297Lys and Glu579Lys.     

The spectrum of factor XI deficiency in Italy

Factor XI (FXI) deficiency is a rare inherited bleeding disorder invariably caused by mutations in the FXI gene. The disorder is rather frequent in Ashkenazi Jews, in whom around 98% of the abnormal alleles is represented by Glu117X and Phe283Leu mutations. A wide heterogeneity of causative mutations has been previously reported in a few FXI deficient patients from Italy. In this article, we enlarge the knowledge on the genetic background of FXI deficiency in Italy. Over 4 years, 22 index cases, eight with severe deficiency and 14 with partial deficiency, have been evaluated. A total of 21 different mutations in 30 disease‐associated alleles were identified, 10 of which were novel. Among them, a novel Asp556Gly dysfunctional mutation was also identified. Glu117X was also detected, as previously reported from other patients in Italy, while again Phe283Leu was not identified. A total of 34 heterozygous relatives were also identified. Bleeding tendency was present in very few cases, being inconsistently related to the severity of FXI deficiency in plasma. In conclusion, at variance with other populations, no single major founder effect is present in Italian patients with FXI deficiency.     

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

Inherited factor XI deficiency is an injury-related bleeding disorder that is rare in most populations except for Jews, in whom 2 mutations, a stop mutation in exon 5 (type II) and a missense mutation in exon 9 (type III), predominate. Recently, a cluster of 39 factor XI-deficient patients was described in the Basque population of Southwestern France. In this study, we determined the molecular basis of factor XI deficiency in 16 patients belonging to 12 unrelated families of French Basque origin. In 8 families, a nucleotide 209T>C transition in exon 3 was detected that predicts a Cys38Arg substitution. Four additional novel mutations in the factor XI gene, Cys237Tyr, Tyr493His, codon 285delG, and IVS6 + 3A>G, were identified in 4 families. Expression studies showed that Cys38Arg and Cys237Tyr factor XI were produced in transfected baby hamster kidney cells, but their secretion was impaired. Cells transfected with Tyr493His contained reduced amounts of factor XI and displayed decreased secretion. A survey of 206 French Basque controls for Cys38Arg revealed that the prevalence of the mutant allele was 0.005. Haplotype analysis based on the study of 10 intragenic polymorphisms was consistent with a common ancestry (a founder effect) for the Cys38Arg mutation.     

A novel mutation (Gln433Glu) in exon 12 combined with the G insertion in exon 13 causes severe factor XI deficiency in Japanese patients.

Factor XI (FXI) deficiency is an autosomal, incompletely recessive coagulopathy. This disorder is rare in the general population worldwide, but is one of the most common inherited diseases in Ashkenazi Jews. It has been reported that a significantly higher frequency of allelic heterogeneity occurs in different ethnic groups. The study objective was to study the molecular basis of this disease in a Japanese family. Two Japanese brothers with severe FXI deficiency and three other family members were screened by direct sequencing analysis after polymerase chain reaction. We identified a novel mutation, a C-to-G transition at position 1394 in exon 12 in the FXI gene (F11 c.1394 C>G). This transition resulted in a missense mutation (Gln433Glu), which led to the disruption of the catalytic domain structure of the FXI molecule. This change, combined with a G insertion in exon 13 (501/502 ins G), led to a frameshift mutation, which has previously been reported in only one other Japanese patient. In conclusion, the compound heterozygous novel mutations that cause severe FXI deficiency were found in Japanese patients.     

A case of factor XI deficiency caused by compound heterozygous F11 gene mutation

Summary.  Inherited factor XI (FXI) deficiency is a rare autosomal recessive bleeding disorder in most populations except for Ashkenazi Jews. In this report, a 25-year-old Chinese female FXI deficiency case has been studied. Routine clotting tests showed significantly prolonged activated partial thromboplastin time (69.5 s, control 35 ± 10 s) while prothrombin time (12.3 s, control 13 ± 3 s) was normal. FXI:C and FXI:Ag were 2.6% and 2.5%, respectively, indicating that this case was cross-reacting material negative. The activities of other coagulation factors and liver function were in normal range. The DNA sequence results of the 15 exons and their boundaries of F11 gene revealed a novel G3733C missense mutation in exon 2, and a recurrent C16642T nonsense mutation in exon 8. The G3733C mutation caused G-1R substitution in FXI signal peptide, which might impair the protein's secretion and introduced a new BssSI enzyme digestion site. The C16642T mutation led a premature stop codon at amino acid position 263(Q263Term). G-1R and Q263Term compound heterozygous mutations in F11 gene were the cause of FXI deficiency for this proband. G-1R mutation was a novel F11 gene mutation causing inherited FXI deficiency.     

Heterozygous factor XI deficiency associated with three novel mutations

To determine the utility of single-stranded conformation polymorphism (SSCP) analysis for screening mutations in the factor XI (fXI) gene, we investigated three patients with heterozygous factor XI deficiency. DNA sequence analysis confirmed three novel mutations; a CGC --> TGC (Arg308Cys) mutation in exon 9, a GCT-->GTT (Ala412Val) mutation in exon 11 and an AGC --> AGA (Ser576Arg) mutation in exon 15. We postulated on the structural implications of these missense mutations. Our results demonstrated that genotypic analysis is a useful tool for conclusive differentiation between heterozygous factor XI deficiency and normal subjects.     

Mendelian diseases among Roman Jews: implications for the origins of disease alleles

The Roman Jewish community has been historically continuous in Rome since pre-Christian times and may have been progenitor to the Ashkenazi Jewish community. Despite a history of endogamy over the past 2000 yr, the historical record suggests that there was admixture with Ashkenazi and Sephardic Jews during the Middle Ages. To determine whether Roman and Ashkenazi Jews shared common signature mutations, we tested a group of 107 Roman Jews, representing 176 haploid sets of chromosomes. No mutations were found for Bloom syndrome, BRCA1, BRCA2, Canavan disease, Fanconi anemia complementation group C, or Tay-Sachs disease. Two unrelated individuals were positive for the 3849 + 10C->T cystic fibrosis mutation; one carried the N370S Gaucher disease mutation, and one carried the connexin 26 167delT mutation. Each of these was shown to be associated with the same haplotype of tightly linked microsatellite markers as that found among Ashkenazi Jews. In addition, 14 individuals had mutations in the familial Mediterranean fever gene and three unrelated individuals carried the factor XI type III mutation previously observed exclusively among Ashkenazi Jews. These findings suggest that the Gaucher, connexin 26, and familial Mediterranean fever mutations are over 2000 yr old, that the cystic fibrosis 3849 + 10kb C->T and factor XI type III mutations had a common origin in Ashkenazi and Roman Jews, and that other mutations prevalent among Ashkenazi Jews are of more recent origin.     

A molecular genetic study of factor XI deficiency

Factor XI deficiency is a rare bleeding diathesis found predominantly in Ashkenazi Jewish kindreds. A recent study of six Jewish patients identified three distinct mutations (Types I, II, and III) in the factor XI gene that were sufficient to fully define the genotypes of the patients. We have investigated 63 patients with factor XI deficiency and find overall allele frequencies of 44% for the type II mutation, 31% for the type III mutation, and 0% for the type I mutation. Therefore, 25% of the mutant factor XI alleles in our sample remain undefined. However, the distribution of mutant alleles is significantly different between Jewish and non-Jewish populations with hitherto undefined mutations accounting for 84% of the disease alleles in non-Jewish patients. Plasma factor XI:C levels were found to differ significantly between different homozygous and compound heterozygous genotypes and the inheritance of the II/III genotype was found to carry an increased risk of the most severe bleeding tendency.     

An Alu-mediated 31.5-kb deletion as the cause of factor XI deficiency in 2 unrelated patients

Factor XI deficiency (MIM 264900) is an autosomal bleeding disorder of variable severity. Inheritance is not completely recessive as heterozygotes may display a distinct, if mild, bleeding tendency. Recent studies have shown the causative mutations of factor XI deficiency, outside the Ashkenazi Jewish population, to be highly heterogeneous. We studied 39 consecutively referred patients with factor XI deficiency to identify the molecular defect. Conventional mutation screening failed to identify a causative mutation in 4 of the 39 patients. Epstein-Barr virus (EBV)-transformed cells from these 4 patients were converted from a diploid to haploid chromosome complement. Subsequent analysis showed that 2 of the patients had a large deletion, which was masked in the heterozygous state by the presence of a normal allele. We report here the first confirmed whole gene deletion as the causative mutation of factor XI deficiency, the result of unequal homologous recombination between flanking Alu repeat sequences.     

Prevalence,causes, and characterization of factor XI inhibitors in patients with inherited factor XI deficiency

Factor XI deficiency, an injury-related bleeding disorder, is rare worldwide but common in Jews in whom 2 mutations, Glu117Stop (type II) and Phe283Leu (type III), prevail. Mean factor XI activities in homozygotes for Glu117Stop and for Phe283Leu are 1 and 10 U/dL, respectively. Inhibitors to factor XI in patients with severe factor XI deficiency have been reported in a small number of instances. This study was undertaken to determine the prevalence of acquired inhibitors against factor XI in patients with severe factor XI deficiency, discern whether these inhibitors are related to specific mutations, and characterize their activity. Clinical information was obtained from unrelated patients with severe factor XI deficiency, and blood was analyzed for factor XI activity, inhibitor to factor XI, and causative mutations. Immunoglobulin G purified from patients with an inhibitory activity was tested for binding to factor XI, effects on activation of factor XI by factor XIIa and thrombin, and activation of factor IX by exogenous factor XIa. Of 118 Israeli patients, 7 had an inhibitor; all belonged to a subgroup of 21 homozygotes for Glu117Stop who had a history of plasma replacement therapy. Three additional patients with inhibitors from the United Kingdom and the United States also had this genotype and were exposed to plasma. The inhibitors affected factor XI activation by thrombin or factor XIIa, and activation of factor IX by factor XIa. The results imply that patients with a very low factor XI level are susceptible to development of an inhibitor following plasma replacement.     

Dominant factor XI deficiency caused by mutations in the factor XI catalytic domain

The bleeding diathesis associated with hereditary factor XI (fXI) deficiency is prevalent in Ashkenazi Jews, in whom the disorder appears to be an autosomal recessive condition. The homodimeric structure of fXI implies that the product of a single mutant allele could confer disease in a dominant manner through formation of heterodimers with wild-type polypeptide. We studied 2 unrelated patients with fXI levels less than 20% of normal and family histories indicating dominant disease transmission. Both are heterozygous for single amino acid substitutions in the fXI catalytic domain (Gly400Val and Trp569Ser). Neither mutant is secreted by transfected fibroblasts. In cotransfection experiments with a wild-type fXI construct, constructs with mutations common in Ashkenazi Jews (Glu117Stop and Phe283Leu) and a variant with a severe defect in dimer formation (fXI-Gly350Glu) have little effect on wild-type fXI secretion. In contrast, cotransfection with fXI-Gly400Val or fXI-Trp569Ser reduces wild-type secretion about 50%, consistent with a dominant negative effect. Immunoprecipitation of cell lysates confirmed that fXI-Gly400Val forms intracellular dimers. The data support a model in which nonsecretable mutant fXI polypeptides trap wild-type polypeptides within cells through heterodimer formation, resulting in lower plasma fXI levels than in heterozygotes for mutations that cause autosomal recessive fXI deficiency.     

Factor XI deficiency

Summary. Although factor XI (FXI) deficiency has a particularly high incidence in Ashkenazi Jews, it is now frequently diagnosed in other ethnic groups. This review gives an overview of the basic pathophysiology, clinical manifestations, and management of FXI deficiency. The correlation between FXI levels and the bleeding phenotype is much less clear than in the haemophilias, and consequently the bleeding risk can be difficult to predict. Two well‐characterized mutations in the F11 gene are responsible for the majority of Jewish cases, but new mutations are becoming increasingly recognized. The publication of the crystal structure has greatly enhanced our understanding of the structure–function relationship in FXI. The impact of recent studies on our understanding of the role of FXI in coagulation is discussed.     

Factor XI deficiency

Factor XI (FXI) deficiency leads to an injury-related bleeding diathesis, which is notable for the variability in the bleeding tendency and the lack of a clear relationship between bleeding and FXI coagulant activity. Bleeding in this disorder occurs especially in areas of high fibrinolytic activity. Although a rare disorder, the frequency of FXI deficiency is high in certain populations, notably persons of Ashkenazi descent and the Basque population of Southern France. In these populations, five mutations of the FXI gene have been identified and a founder effect has been confirmed for three of these. This paper reviews the role of FXI in coagulation and documents factors known to modify the bleeding tendency. Treatment of surgical bleeding in patients with FXI deficiency is reviewed with emphasis on the combined use of recombinant activated factor VII (rFVIIa; NovoSeven®, Novo Nordisk, Bagsvaerd, Denmark) and the antifibrinolytic agent, tranexamic acid.     

New observations on factor XI deficiency

Summary.  Factor (F) XI is an injury-related bleeding tendency that commonly occurs when trauma involves tissues rich in fibronolytic activators. Severe FXI deficiency is defined when the activity of FXI in plasma is less than 15 U dL⁻¹. The disorder is inherited as an autosomal recessive trait manifesting in homozygotes or compound heterozygotes, and infrequently in heterozygotes. So far 53 mutations in the gene of FXI have been described and four of them were found to be prevalent in Ashkenazi Jews, Iraqi Jews, Basques or the English population. For each of the four mutations a founder effect was discerned. Inhibitors can develop in patients with FXI level < 1U dL⁻¹ who were exposed to plasma which seriously complicates their management during surgery. No correction of a prolonged aPTT by normal plasma is indicative of the presence of an inhibitor. In contrast to patients with haemophilia A, severe FXI deficiency provides no protection against myocardial infarction. In patients with severe FXI deficiency undergoing surgery, fresh frozen plasma is the treatment of choice. FXI concentrates can also be used but cause thrombosis in approximately 10% of patients, particularly those with cardiovascular disease. Recombinant FVIIa has successfully prevented bleeding during or after surgery in patients with FXI inhibitors.