FACTOR XI DEFICIENCY IN AN ARAB FAMILY NOT DUE TO THE COMMON TYPE II OR III MUTATIONS. 968

Abstract Factor XI deficiency (MIM 264900) is an autosomal bleeding disorder of variable clinical severity. In contrast to haemophilia A or B the clinical symptoms do not correlate well with plasma levels of factor XI; it is therefore difficult to predict the bleeding tendency from either the factor level or the molecular defect. FXI deficiency is particularly common in the Ashkenazi Jews with a heterozygous frequency of ~9%, associated with two common founder mutations - E117X (Type II) and F283L (Type III). Recent studies have shown that mutations causing Factor XI deficiency are heterogeneous outside the Ashkenazi Jewish population. We have studied 116 index cases from an ethnically diverse U.K. population in order to better understand the spectrum of mutations responsible for factor XI deficiency. Of the index cases, 25 were of Ashkenazi Jewish ancestry, 2 were of Afro-Caribbean origin, 9 Asian, 3 Arabic, 1 New Zealand Maori and 73 white Caucasian; ancestry was unknown in three patients. We have identified a total of 141 causative mutations in 107 patients. Of the nine patients in whom a mutation remained unidentified, six were reproducibly factor XI deficient with no evidence of inhibitors, but in three the diagnosis was inconclusive. The 141 mutations included 54 different sequence variants and 5 whole gene deletions of which there are at least two forms. Of the variants, forty-one are missense mutations, eight nonsense mutations, four splice site mutations and one small deletion. Twenty-seven of these varients are novel and reported here for the first time. Three common mutations were identified, with similar frequencies. The Type II mutation (E117X) accounted for 14.9% of the total mutations, the Type III mutation (F283L) 12.1% and the C128X “UK mutation” 11.3%. Together these three mutations account for more than a third (38.3%) of the total. Outside of these three ‘common’ mutations, no other mutation was identified in more than 3 individuals. Despite the heterogeneous nature of factor XI mutations, with mutations being identified in all 15 exons of the factor XI gene, almost two thirds (65%) of the mutations could be covered in just 3 amplicons - exons 5, 15 and 8/9/10. All patients with Ashkenazi Jewish ancestry had Type II and/or Type III mutations. Three Jewish patients were compound heterozygous for the Type II mutation and another ‘non-Jewish’ mutation. One Arabic patient was homozygous for the Type II mutation. The C128X mutation was only identified in patients with a clear British ancestry. However, not all repeat mutations were restricted to a single ethnic group. Four mutations were identified in more than one ethnic group, three of which were located at CpG sites. This study confirms the ethnic and molecular heterogeneity of factor XI deficiency despite its historical association with the Ashkenazi Jewish population and the Type II & Type III mutations. Our study also reinforces the difficulty of predicting clinical phenotype from molecular defect in factor XI deficiency.

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

Blood ◽

10.1182/blood.v99.7.2448 ◽

2002 ◽

Vol 99 (7) ◽

pp. 2448-2454 ◽

Cited By ~ 77

Author(s):

Ariella Zivelin ◽

Frederic Bauduer ◽

Louis Ducout ◽

Hava Peretz ◽

Nurit Rosenberg ◽

...

Keyword(s):

Haplotype Analysis ◽

Kidney Cells ◽

Type Ii ◽

Novel Mutations ◽

Factor Xi ◽

Factor Xi Deficiency ◽

Expression Studies ◽

Stop Mutation ◽

Exon 9 ◽

Baby Hamster Kidney Cells

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.

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The Two Common Mutations Causing Factor XI Deficiency in Jews Stem From Distinct Founders: One of Ancient Middle Eastern Origin and Another of More Recent European Origin

Blood ◽

10.1182/blood.v90.7.2654 ◽

1997 ◽

Vol 90 (7) ◽

pp. 2654-2659 ◽

Cited By ~ 66

Author(s):

Hava Peretz ◽

Avital Mulai ◽

Sali Usher ◽

Ariella Zivelin ◽

Avihai Segal ◽

...

Keyword(s):

Middle Eastern ◽

Allele Frequencies ◽

Initial Population ◽

Type Ii ◽

Ashkenazi Jewish ◽

Ashkenazi Jews ◽

Factor Xi ◽

Factor Xi Deficiency ◽

Type Iii ◽

Frequent Mutations

Abstract Previous studies showed that factor XI (FXI) deficiency commonly observed in Ashkenazi Jews is caused by two similarly frequent mutations, type II (Glu117stop) and type III (Phe283Leu) with allele frequencies of 0.0217 and 0.0254, respectively. In Iraqi Jews, who represent the ancient gene pool of Jews, only the type II mutation was observed with an allele frequency of 0.0167. In this study we sought founder effects for each mutation by examination of four FXI gene polymorphisms enabling haplotype analysis in affected Jewish patients of Ashkenazi, Iraqi, and other origins and in Arab patients. Initial population surveys of 387 Middle Eastern Jews (excluding Iraqi Jews), 560 North African/Sephardic Jews, and 382 Arabs revealed allele frequencies for the type II mutation of 0.0026, 0.0027, and 0.0065, respectively. In contrast, the type III mutation was not detected in any of these populations. All 60 independent chromosomes bearing the type III mutation were solely observed in Ashkenazi Jewish patients and were characterized by a relatively rare haplotype. All 103 independent chromosomes bearing the type II mutation in patients of Ashkenazi, Iraqi, Yemenite, Syrian, and Moroccan Jewish origin and of Arab origin were characterized by another distinct haplotype that was rare among normal Ashkenazi Jewish, Iraqi Jewish, and Arab chromosomes. These findings constitute the first example of a mutation common to Ashkenazi Jews, non-Ashkenazi Jews, and Arabs and are consistent with the origin of type II mutation in a founder before the divergence of the major segments of Jews. Our findings also indicate that the type III mutation arose more recently in an Ashkenazi Jewish individual.

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The Two Common Mutations Causing Factor XI Deficiency in Jews Stem From Distinct Founders: One of Ancient Middle Eastern Origin and Another of More Recent European Origin

Blood ◽

10.1182/blood.v90.7.2654.2654_2654_2659 ◽

1997 ◽

Vol 90 (7) ◽

pp. 2654-2659 ◽

Cited By ~ 1

Author(s):

Hava Peretz ◽

Avital Mulai ◽

Sali Usher ◽

Ariella Zivelin ◽

Avihai Segal ◽

...

Keyword(s):

Middle Eastern ◽

Allele Frequencies ◽

Initial Population ◽

Type Ii ◽

Ashkenazi Jewish ◽

Ashkenazi Jews ◽

Factor Xi ◽

Factor Xi Deficiency ◽

Type Iii ◽

Frequent Mutations

Previous studies showed that factor XI (FXI) deficiency commonly observed in Ashkenazi Jews is caused by two similarly frequent mutations, type II (Glu117stop) and type III (Phe283Leu) with allele frequencies of 0.0217 and 0.0254, respectively. In Iraqi Jews, who represent the ancient gene pool of Jews, only the type II mutation was observed with an allele frequency of 0.0167. In this study we sought founder effects for each mutation by examination of four FXI gene polymorphisms enabling haplotype analysis in affected Jewish patients of Ashkenazi, Iraqi, and other origins and in Arab patients. Initial population surveys of 387 Middle Eastern Jews (excluding Iraqi Jews), 560 North African/Sephardic Jews, and 382 Arabs revealed allele frequencies for the type II mutation of 0.0026, 0.0027, and 0.0065, respectively. In contrast, the type III mutation was not detected in any of these populations. All 60 independent chromosomes bearing the type III mutation were solely observed in Ashkenazi Jewish patients and were characterized by a relatively rare haplotype. All 103 independent chromosomes bearing the type II mutation in patients of Ashkenazi, Iraqi, Yemenite, Syrian, and Moroccan Jewish origin and of Arab origin were characterized by another distinct haplotype that was rare among normal Ashkenazi Jewish, Iraqi Jewish, and Arab chromosomes. These findings constitute the first example of a mutation common to Ashkenazi Jews, non-Ashkenazi Jews, and Arabs and are consistent with the origin of type II mutation in a founder before the divergence of the major segments of Jews. Our findings also indicate that the type III mutation arose more recently in an Ashkenazi Jewish individual.

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

Thrombosis and Haemostasis ◽

10.1055/s-0037-1614125 ◽

2000 ◽

Vol 84 (11) ◽

pp. 833-840 ◽

Cited By ~ 20

Author(s):

Célia Ventura ◽

Ana I. Santos ◽

Alice Tavares ◽

Teresa Gago ◽

João Lavinha ◽

...

Keyword(s):

Genetic Analysis ◽

Molecular Genetic ◽

Coagulation Factor ◽

Molecular Genetic Analysis ◽

Null Alleles ◽

Type Ii ◽

Factor Xi ◽

Factor Xi Deficiency ◽

Premature Termination Codons ◽

Gene Alterations

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.

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A novel factor XI missense mutation (Val371Ile) in the activation loop is responsible for a case of mild type II factor XI deficiency

FEBS Journal ◽

10.1111/j.1742-4658.2007.06134.x ◽

2007 ◽

Vol 274 (23) ◽

pp. 6128-6138 ◽

Cited By ~ 3

Author(s):

Cristina Bozzao ◽

Valeria Rimoldi ◽

Rosanna Asselta ◽

Meytal Landau ◽

Rossella Ghiotto ◽

...

Keyword(s):

Missense Mutation ◽

Activation Loop ◽

Type Ii ◽

Factor Xi ◽

Factor Xi Deficiency

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Patients with Severe Factor XI Deficiency Have a Reduced Incidence of Venous Thromboembolism.

Blood ◽

10.1182/blood.v114.22.3491.3491 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3491-3491 ◽

Cited By ~ 1

Author(s):

Ophira Salomon ◽

Ariella Zivelin ◽

Ilia Tamarin ◽

David M. Steinberg ◽

David Varon ◽

...

Keyword(s):

Venous Thromboembolism ◽

Incidence Rate ◽

Factor V Leiden ◽

Prothrombin G20210a ◽

Factor V ◽

Factor Xi ◽

Factor Xi Deficiency ◽

G20210a Mutation ◽

Increased Risk ◽

The Common

Abstract Abstract 3491 Poster Board III-428 Patients with severe factor XI deficiency (level ≤15U/dL) were recently found to be protected against ischemic stroke but not against myocardial infarction (Blood 2008, 111:4113). Regarding venous thrombosis, several clinical and experimental observations suggest that factor XI deficiency might confer protection. Thus, only 2 patients with severe factor XI deficiency have been reported with unprovoked venous thromboembolism, and protection against FeCl3 Cinduced thrombosis in the vena cava was observed in factor XI deficient mice (J Thromb Haemost 2006, 4:1982). Other studies established that an increased level of factor XI is associated with an increased risk of venous thromboembolism. In the present study, we investigated whether patients with severe factor XI deficiency are protected against venous thromboembolism. We interviewed 222 unrelated patients with severe FXI deficiency and reviewed their medical charts. In the cohort, there were 126 females and 96 males aged 20-94 years of whom 137 were 50 years or older. The expected incidence rates of venous thromboembolism in the general population for males and females at different age groups were extracted from a population-based study of venous thromboembolism (J Thromb Haemost 2007,5:692). The expected incidence rate of venous thromboembolism in the factor XI deficiency cohort was 4.67 (2.37 in females and 2.30 in males), while the observed incidence rate was 0/222. This difference was statistically significant taking into account age and sex by the Poisson test (p=0.036). The prevalence of the common inherited thrombophilias was examined in 194 of the 222 patients. Seven (3.6%) patients harbored factor V Leiden, and 17 (8.8%) harbored the prothrombin G20210A mutation; the corresponding proportions in the general Israeli population are 3.9% for factor V Leiden, and 5.4% for prothrombin G20210A mutation. Thus, there was no decreased prevalence of the common thrombophilias in the factor XI deficient cohort. Collectively, the data suggest that patients with severe factor XI deficiency are protected against venous thromboembolism. Disclosures: No relevant conflicts of interest to declare.

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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]

Blood ◽

10.1182/blood.v85.2.429.bloodjournal852429 ◽

1995 ◽

Vol 85 (2) ◽

pp. 429-432 ◽

Cited By ~ 1

Author(s):

O Shpilberg ◽

H Peretz ◽

A Zivelin ◽

R Yatuv ◽

A Chetrit ◽

...

Keyword(s):

Allele Frequency ◽

Gene Pool ◽

Type Ii ◽

Ashkenazi Jewish ◽

Ashkenazi Jews ◽

Factor Xi ◽

Factor Xi Deficiency ◽

Type Iii ◽

Estimated Risk ◽

Ancient Gene

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.

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Computational studies to identify the common type‐I and type‐II inhibitors against the CDK8 enzyme

Journal of Cellular Biochemistry ◽

10.1002/jcb.30209 ◽

2022 ◽

Author(s):

Amar Ghosh ◽

Anu Manhas ◽

Prakash C. Jha

Keyword(s):

Common Type ◽

Type I ◽

Computational Studies ◽

Type Ii ◽

The Common

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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]

Blood ◽

10.1182/blood.v85.2.429.429 ◽

1995 ◽

Vol 85 (2) ◽

pp. 429-432 ◽

Cited By ~ 84

Author(s):

O Shpilberg ◽

H Peretz ◽

A Zivelin ◽

R Yatuv ◽

A Chetrit ◽

...

Keyword(s):

Allele Frequency ◽

Gene Pool ◽

Type Ii ◽

Ashkenazi Jewish ◽

Ashkenazi Jews ◽

Factor Xi ◽

Factor Xi Deficiency ◽

Type Iii ◽

Estimated Risk ◽

Ancient Gene

Abstract 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.

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