Alternative titles; symbols
HGNC Approved Gene Symbol: F11
SNOMEDCT: 49762007; ICD10CM: D68.1; ICD9CM: 286.2;
Cytogenetic location: 4q35.2 Genomic coordinates (GRCh38): 4:186,266,189-186,289,681 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q35.2 | Factor XI deficiency, autosomal dominant | 612416 | 3 | |
| Factor XI deficiency, autosomal recessive | 612416 | 3 |
Factor XI is a glycoprotein that circulates in plasma as a noncovalent complex with high molecular weight kininogen (HMWK; see 612358). It is converted to an active protease, factor XIa, by factor XIIa (F12; 610619). It participates in blood coagulation as a catalyst in the conversion of factor IX to factor IXa in the presence of calcium ions (Asakai et al., 1987).
Fujikawa et al. (1986) cloned a human F11 cDNA from a liver cDNA library. The deduced F11 protein contains a leader peptide of 18 amino acids followed by 607 amino acids. The mature protein of 1,214 amino acids that circulates in plasma is formed by 2 of these polypeptide chains linked by a disulfide bond. Each chain contains 5 potential N-glycosylation sites. Each heavy chain of factor XIa (369 amino acids) contains 4 tandem repeats of 90 or 91 amino acids plus a short connecting peptide. Each light chain of factor XIa (238 amino acids) contains the catalytic portion of the enzyme with sequences typical of the trypsin family of serine proteases. Factor XI shares 58% amino acid sequence identity with plasma prekallikrein (229000).
Fujikawa et al. (1986) demonstrated that the cleavage site for the activation of factor XI by factor XIIa is an internal peptide bond between arg369 and ile370 in each F11 chain.
By in situ hybridization using a genomic DNA probe that contained exons 8, 9, and 10 of the F11 gene, Kato et al. (1989) assigned F11 to chromosome 4q35. Buetow et al. (1991) confirmed the mapping by family linkage studies using DNA markers.
Asakai et al. (1987) determined that the gene for human factor XI is 23 kb long and contains 15 exons. Exon 1 codes for the 5-prime untranslated region and exon 2 for the signal peptide. The authors compared the organization of the F11 gene to those of several other serine proteinases.
Tarumi et al. (2002) cloned and characterized the promoter region of the F11 gene. Luciferase reporter assays demonstrated that the 381 basepairs upstream of exon 1 were sufficient for maximum promoter activity in HepG2 hepatocellular carcinoma cells. Gel mobility shift assays using HepG2 cells confirmed binding of transcription factor hepatocyte nuclear factor-4A (HNF4A; 600281) to an ACTTTG motif between bp -375 and -360 of the F11 promoter. Scrambling of the motif completely abolished promoter activity. The F11 promoter functioned poorly when transfected into HeLa carcinoma cells, and gel mobility shift experiments with HeLa nuclear extracts demonstrated no HNF4A binding to the ACTTTG sequence. When a rat HNF4A expression construct was cotransfected into HeLa cells, F11 promoter activity was enhanced approximately 10-fold. Tarumi et al. (2002) concluded that HNF4A is required for hepatocyte-specific expression of factor XI.
Asakai et al. (1989) identified 3 independent point mutations in the F11 gene of 6 unrelated Ashkenazi patients with factor XI deficiency (612416): a splice site mutation (264900.0001), a nonsense mutation (264900.0002), and a missense mutation (264900.0003). No correlation could be demonstrated between the specific genotype and the bleeding tendency in the subjects studied. In a survey of 53 apparently normal, unrelated Ashkenazi Jews, Asakai et al. (1989) found 2 who were heterozygous for the missense mutation. None had the splicing or nonsense mutation.
Peretz et al. (1993) described a mutation in the F11 gene in an Ashkenazi Jewish patient. Pugh et al. (1995) reported 6 additional F11 mutations in patients with factor 11 deficiency (see, e.g., 264900.0004 and 264900.0005) and noted that 5 mutations had been identified in non-Ashkenazi patients, 2 in Japanese patients and 3 in English patients.
Mitchell et al. (1999) performed SSCP analysis of the F11 gene in 3 patients with heterozygous factor XI deficiency. Three missense mutations were found: arg308 to cys (264900.0009), ala412 to val (264900.0010), and ser576 to arg (264900.0011). In these 3 patients the factor XI antigen level varied from 22.9 to 38.6 and factor XI activity varied from 27 to 50%. They speculated about the mechanism by which these mutations in heterozygous state lead to clinical manifestations.
Salomon et al. (2003) undertook a study to determine the prevalence of acquired inhibitors against factor XI in patients with severe factor XI deficiency, discerned whether these inhibitors are related to specific mutations, and characterized their activity. Of 118 Israeli patients, 7 had an inhibitor; all belonged to a subgroup of 21 homozygotes for glu117-to-ter (264900.0002) who had a history of plasma replacement therapy. Three additional patients with inhibitors from the UK and the US 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.
In each of 2 unrelated patients with factor XI levels less than 20% of normal and with family histories indicating dominant disease transmission, Kravtsov et al. (2004) identified heterozygosity for a missense mutation in the F11 gene (264900.0014-264900.0015). The mutants were not secreted by transfected fibroblasts. In cotransfection experiments with a wildtype factor XI construct, constructs with the mutations reduced wildtype secretion approximately 50%, consistent with a dominant-negative effect. The data supported a model in which nonsecretable mutant factor XI polypeptides trap wildtype polypeptides within cells through heterodimer formation, resulting in lower plasma factor XI levels than in heterozygotes for mutations that cause autosomal recessive factor XI deficiency.
Hill et al. (2005) identified 12 different mutations in the F11 gene in 30 patients from 13 unrelated non-Jewish families with factor XI deficiency. One of the mutations resulted in a full gene deletion (264900.0016).
In an Ashkenazi Jewish patient with factor XI deficiency (612416), Asakai et al. (1989) identified compound heterozygosity for 2 mutations in the F11 gene: a G-to-A substitution at position +1 in intron 14 and a glu117-to-ter mutation (E117X; 264900.0002).
In 4 Ashkenazi Jewish patients with factor XI deficiency (612416), Asakai et al. (1989) identified compound heterozygosity for 2 mutations in the F11 gene: a G-to-T transversion in exon 5, resulting in a glu117-to-ter (E117X) substitution, and a T-to-C transition in exon 9, resulting in a phe283-to-leu substitution (F283L; 264900.0003). In another Ashkenazi Jewish patient, they identified compound heterozygosity for the E117X mutation and a splice site mutation (264900.0001).
This variant is found in Iraqi Jews, among whom factor XI deficiency is rare. Asakai et al. (1991) found this mutation in 49% of 86 alleles examined from Ashkenazi Jews in Israel.
For discussion of the phe283-to-leu (F283L) mutation in the F11 gene that was found in compound heterozygous state in patients with factor XI deficiency (612416) by Asakai et al. (1989), see 264900.0002.
Asakai et al. (1991) found this variant in 47% of 86 alleles examined from Ashkenazi Jews. They found that patients homozygous for this mutation had a significantly higher level of factor XI clotting activity as well as significantly fewer episodes of injury-related bleeding than those homozygous for the E117X mutation (264900.0002) or compound heterozygotes for both mutations. Each of these 3 groups had a similarly increased proportion of episodes of bleeding complications after surgery at sites with enhanced local fibrinolysis, such as the urinary tract, or during tooth extraction.
Meijers et al. (1992) characterized this mutant factor XI in an in vitro expression system.
Pugh et al. (1995) identified an A-to-G mutation at the second to last base of intron 9 in the F11 gene in a patient with factor XI deficiency (612416). This AG-to-GG change at the 3-prime splice junction site is the type of change that has been observed as the cause of several disorders, such as beta-thalassemia (613985), when it occurs in the HBB gene (see 141900); familial type III hyperlipoproteinemia, when it occurs in the APOE gene (107741.0005); and analbuminemia, when it occurs in the ALB gene (103600.0027).
In a patient with factor XI deficiency (612416), Pugh et al. (1995) identified a G-to-C transversion at the fifth base of intron 5 following exon 5. G is the fifth base in 82% of the introns of known eukaryotic nuclear genes; changing the base at this position reduces the levels of mature mRNA obtained in in vitro studies.
Imanaka et al. (1995) studied 2 unrelated non-Jewish patients with CRM-negative factor XI deficiency (612416). Their F11 genes were screened by SSCP analysis following PCR amplification of each exon and the flanking intronic sequences. DNA fragments showing aberrant mobility were cloned and sequenced. In the first patient, a T-to-G transversion in exon 12 resulted in a phe442-to-val substitution (F442V). This mutation resulted in a substitution within the protease domain of factor XI. Both individuals were heterozygous for the mutations and had only mild bleeding tendency. Case 1, a 37-year-old female, was found to have a prolonged activated partial thromboplastin time (APTT) when screened before starting oral anticoagulant therapy in connection with mitral valve disease. She had always bruised easily, but had wisdom teeth extracted without excessive bleeding and gave birth to 2 children uneventfully. She had had heavy menstrual periods. The father and a paternal uncle had excessive bleeding after dental extractions and adenotonsillectomy and had intermediate levels of factor XI. Also see 264900.0007.
One of 2 unrelated non-Jewish patients with CRM-negative factor XI deficiency (612416) studied by Imanaka et al. (1995) had a heterozygous C-to-A transition in exon 5 of the F11 gene, resulting in a cys128-to-ter (C128X) substitution. He was a 50-year-old man who bled excessively after submucosal resection of the nasal septum at age 34 and after dental extractions at age 17. The mutation was predicted to cause factor XI deficiency by mRNA instability and/or incorrect folding of the truncated protein. Also see 264900.0006.
Dai et al. (2004) found the C128X mutation in compound heterozygosity with a missense mutation (K252I; 264900.0013) in 2 related patients of European Caucasian extraction. These 2 patients had no active bleeding problems following laparoscopic sterilization. Preoperative laboratory tests revealed a prolonged activated partial thromboplastin time.
In an 8-year-old Arab girl with factor XI deficiency (612416) whose family was from east Jerusalem, Wistinghausen et al. (1997) identified a homozygous 1254C-A mutation in exon 11 of the F11 gene, resulting in a thr386-to-asn (T386N) substitution. The authors postulated that the substitution interfered with folding and secretion of the molecule. One sib and the father also had severe factor XI deficiency. Both the proposita's and her father's parents were first cousins. Thus, this was an example of pseudodominance.
In a patient with a history of easy bruising, who was referred for study because adenotonsillectomy was proposed and a bleeding risk was perceived (612416), Mitchell et al. (1999) identified a heterozygous arg308-to-cys (R308C) mutation caused by a CGC-to-TGC transition in exon 9 of the F11 gene.
Mitchell et al. (1999) studied a patient who had menorrhagia for 2 years and recent dental work that left her with large facial bruising and nosebleeds. She was found to have factor XI levels in the heterozygous range (612416) and a heterozygous ala412-to-val (A412V) mutation due to a GCT-to-GTT transition in exon 11 of the F11 gene.
Mitchell et al. (1999) did molecular analysis of the F11 gene in a patient who suffered a hemorrhage following cervical erosion and had miscarried during her second trimester after experiencing pregnancy-associated bleeding (612416). They found a heterozygous C-to-A transversion in exon 15, resulting in a ser576-to-arg (S576R) substitution.
Bauduer et al. (1999) identified a cluster of 39 individuals with factor XI deficiency (612416) among Basques residing in southern France. Zivelin et al. (2002) determined the molecular basis of factor XI deficiency in 16 patients belonging to 12 unrelated French Basque families. In 8 families, a heterozygous 209T-C transition in exon 3 of the F11 gene resulted in a cys38-to-arg (C38R) substitution. A survey of 206 French Basque controls revealed that the prevalence of the mutant allele was 0.005. Haplotype analysis based on a study of 10 intragenic polymorphisms was consistent with a common ancestry (founder effect) for the C38R mutation. The other 4 French Basque families with factor XI deficiency each had a novel mutation.
In 2 related patients of European Caucasian extraction with factor XI deficiency (612416), Dai et al. (2004) identified compound heterozygosity for 2 mutations in the F11 gene: an A-to-T transversion in exon 8, resulting in a lys252-to-ile (K252I) substitution, and a C128X (264900.0007) mutation. Severe factor XI deficiency was discovered on preoperative laboratory tests, but the patients had no active bleeding problems following laparoscopic sterilization. Expression studies in transfected BHK cells indicated that although the mutant protein was synthesized, secretion was reduced. The substitution of ile, a neutrally charged hydrophobic amino acid, for lys, a positively charged hydrophilic amino acid, alters charge and polarity within the third apple domain of factor XI. Dai et al. (2004) suggested that this may cause unstable conformation of the factor XI molecule, interfering with secretion.
In a patient with factor XI levels less than 20% of normal and with a family history indicating dominant transmission of factor XI deficiency (612416), Kravtsov et al. (2004) identified a heterozygous 1296G-T transversion in exon 11 of the F11 gene, resulting in a gly400-to-val (G400V) substitution. The mutant was not secreted by transfected fibroblasts. In cotransfection experiments with a wildtype factor XI construct, constructs with the mutation reduced wildtype secretion approximately 50%, consistent with a dominant-negative effect.
In a patient with factor XI levels less than 20% of normal and with a family history indicating dominant transmission of factor XI deficiency (612416), Kravtsov et al. (2004) identified a heterozygous 1804G-C transversion in exon 15 of the F11 gene, resulting in a trp569-to-ser (W569S) substitution. The mutant was not secreted by transfected fibroblasts. In cotransfection experiments with a wildtype factor XI construct, constructs with the mutation reduced wildtype secretion approximately 50%, consistent with a dominant-negative effect. The patient's father, whose factor XI levels were 25 to 30% of normal, also carried the W569S mutation.
In 9 affected members of a family with factor XI deficiency (612416), Hill et al. (2005) identified a heterozygous 31.5-kb Alu-mediated whole-gene deletion of the F11 gene. The phenotype was similar to that reported for other patients with factor XI deficiency.
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Kato, A., Asakai, R., Davie, E. W., Aoki, N. Factor XI gene (F11) is located on the distal end of the long arm of human chromosome 4. Cytogenet. Cell Genet. 52: 77-78, 1989. [PubMed: 2612218] [Full Text: https://doi.org/10.1159/000132844]
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Salomon, O., Zivelin, A., Livnat, T., Dardik, R., Loewenthal, R., Avishai, O., Steinberg, D. M., Rosove, M. H., O'Connell, N., Lee, C. A., Seligsohn, U. Prevalence, causes, and characterization of factor XI inhibitors in patients with inherited factor XI deficiency. Blood 101: 4783-4788, 2003. [PubMed: 12586617] [Full Text: https://doi.org/10.1182/blood-2002-09-2794]
Tarumi, T., Kravtsov, D. V., Zhao, M., Williams, S. M., Gailani, D. Cloning and characterization of the human factor XI gene promoter: transcription factor hepatocyte nuclear factor 4-alpha (HNF-4-alpha) is required for hepatocyte-specific expression of factor XI. J. Biol. Chem. 277: 18510-18516, 2002. [PubMed: 11891231] [Full Text: https://doi.org/10.1074/jbc.M201886200]
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Zivelin, A., Bauduer, F., Ducout, L., Peretz, H., Rosenberg, N., Yatuv, R., Seligsohn, U. Factor XI deficiency in French Basques is caused predominantly by an ancestral cys38-to-arg mutation in the factor XI gene. Blood 99: 2448-2454, 2002. [PubMed: 11895778] [Full Text: https://doi.org/10.1182/blood.v99.7.2448]