HGNC Approved Gene Symbol: F10
SNOMEDCT: 76642003;
Cytogenetic location: 13q34 Genomic coordinates (GRCh38): 13:113,122,799-113,149,529 (from NCBI)
Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
---|---|---|---|---|
13q34 | Factor X deficiency | 227600 | Autosomal recessive | 3 |
The F10 gene encodes coagulation factor X, which is the zymogen of factor Xa, a serine protease that occupies a pivotal position in the clotting process. It is activated either by the contact-activated (intrinsic) pathway or by the tissue factor (extrinsic) pathway. Factor Xa, in combination with factor V (F5; 612309), then activates prothrombin (F2; 176930) to form the effector enzyme of the coagulation cascade (review by Cooper et al., 1997).
Enfield et al. (1975) showed that the amino-terminal sequence of the light chain of bovine factor X, which they referred to as 'Stuart factor,' is homologous with the amino-terminal region of bovine prothrombin and, like the latter, appears to contain several residues of the unusual amino acid, gamma-carboxyglutamic acid (Gla). The heavy chains of bovine factors X and IX (F9; 300746) are homologous with trypsin, thrombin, and other mammalian serine proteases.
Leytus et al. (1984) isolated and characterized a cDNA coding for human factor X. The DNA sequence coding for the active site showed a high degree of homology with prothrombin and factor IX, 2 other vitamin K-dependent serine proteases that participate in blood coagulation. Factor X is synthesized in the liver as a single-chain molecule. It is composed of a 16.2-kD light chain and a 45-kD heavy chain held together by a disulfide bond. Vitamin K is involved in the biosynthesis, and is required for the carboxylation of the first 11 glutamic acid residues in the amino-terminal portion of the light chain. The heavy chain contains the catalytic domain (see also summary by Millar et al., 2000).
Fung et al. (1985) predicted the amino acid factor X sequence of plasma factor X from the cDNA. Factor X is synthesized as a single polypeptide chain precursor in which the light and heavy chains are linked by the tripeptide arg-lys-arg.
Leytus et al. (1986) reported that the F10 gene contains 8 exons and spans approximately 25 kb of genomic DNA. The gene shows considerable structural homology with genes encoding other vitamin K-dependent clotting factors. Exon 1 codes for the signal peptide, exon 2 for the propeptide and the Gla-rich domain, exon 3 for the short aromatic acid-rich stack, exon 4 for the first epidermal growth factor (EGF) domain, exon 5 for the second EGF domain, exon 6 for the activation peptide, and exons 7 and 8 for the catalytic domain. Human F10 mRNA comprises approximately 1,500 nucleotides, including a coding region of 1,475 bases and a short 3-prime untranslated region of 10 nucleotides. The polyadenylation signal (ATTAAA) is located in the coding sequence and precedes the stop codon by 1 nucleotide. It appears that the vitamin K-dependent proteins evolved from a single common gene and that this ancestral gene arose through a process involving the assembly of small protein coding units.
By Southern analysis of somatic cell hybrids, Royle et al. (1985) assigned the F10 gene to chromosome 13. Rocchi et al. (1985, 1986) confirmed the assignment of F10 to chromosome 13 by means of blotting studies of DNA from somatic cell hybrids using a cDNA probe. By in situ hybridization, Royle et al. (1986) mapped factor X to 13q32-qter.
By dosage effects in 7 cases of abnormal chromosome 13, Gilgenkrantz et al. (1986) mapped the F7 (613878) and F10 genes to 13q34. The clotting factors were increased in trisomy of this segment and decreased in monosomy.
In constructing the CEPH consortium linkage map of chromosome 13, Bowcock et al. (1993) concluded that F10 is the most telomeric marker on that chromosome.
Using interspecific and intersubspecific mapping panels, Koizumi et al. (1995) mapped the mouse homolog, Cf10, to the centromeric region of mouse chromosome 8.
Other vitamin K-dependent proteins known to be involved in blood coagulation are factor VII (613878), factor IX (300746), prothrombin (176930), protein S (PROS1; 176880), and protein C (PROC; 612283). Synthesis of factors VII and X, as well as factors II and IX, takes place in the liver and requires vitamin K. Structural homologies of these factors, which are precursors of serine proteases, have been shown (Zur and Nemerson, 1981). Ratnoff and Bennett (1973) stated: 'Although a persuasive argument can be made that (they) are derived from a single molecule most evidence suggests that they are distinctive proteins.'
The Gla domain of blood coagulation factors such as factor X is responsible for Ca(2+)-dependent phospholipid membrane binding. Factor X-binding protein, an anticoagulant protein from snake venom, specifically binds to the Gla domain of factor X. Mizuno et al. (2001) reported that the crystal structure of factor X-binding protein in complex with the Gla domain peptide of factor X shows that the anticoagulation is based on the fact that 2 patches of the Gla domain essential for membrane binding are buried in the complex formation. The Gla domain could thus be a new target of anticoagulant drugs, and the anticoagulant protein from snake venom could provide a basis for designing them.
Doronin et al. (2012) modeled the interface of human species C adenovirus (HAdv) interaction with coagulation factor X and introduced a mutation that abrogated formation of the HAdv-FX complex. In vivo genomewide transcriptional profiling revealed that FX binding-ablated virus failed to activate a distinct network of nuclear factor kappa-B (see 164011)-dependent early response genes that are activated by HAdv-FX complex downstream of TLR4 (603030)/MyD88 (602170)/TRIF (607601)/TRAF6 (602355) signaling. Doronin et al. (2012) concluded that their study implicated host factor 'decoration' of the virus as a mechanism to trigger an innate immune sensor that responds to a misplacement of coagulation factor X from the blood into intracellular macrophage compartments upon virus entry into the cell.
Ghorpade et al. (2018) showed that obesity in mice stimulates hepatocytes to synthesize and secrete dipeptidyl peptidase-4 (DPP4; 102720), which acts with plasma factor Xa to inflame adipose tissue macrophages. Silencing expression of DPP4 in hepatocytes suppressed inflammation of visceral adipose tissue and insulin resistance; however, a similar effect was not seen with the orally administered DPP4 inhibitor sitagliptin. Inflammation and insulin resistance were also suppressed by silencing expression of caveolin-1 (601047) or PAR2 (600933) in adipose tissue macrophages; these proteins mediate the actions of DPP4 and factor Xa, respectively. Ghorpade et al. (2018) concluded that hepatocyte DPP4 promotes visceral adipose tissue inflammation and insulin resistance in obesity, and that targeting this pathway may have metabolic benefits that are distinct from those observed with oral DPP4 inhibitors.
Polymorphism of factors IX and X was suggested by the findings of Lester et al. (1972).
Siervogel et al. (1979) concluded from pedigree analysis that an autosomal, 2-allele locus may determine the level of factor X. The allele for low factor X activity appeared to be dominant and the frequency of the dominant allele was estimated to be 0.53. In an editorial on variants of vitamin K-dependent coagulation factors, Bertina et al. (1979) stated that 9 defective variants of factor II, 5 variants of factor X, and many variants (about 180 pedigrees) of factor IX had been identified.
Factor X Deficiency
In a patient with a bleeding disorder due to factor X deficiency (227600), Reddy et al. (1989) identified compound heterozygosity for 2 mutations in the F10 gene (613872.0001 and 613872.0002). The patient had prolonged bleeding after surgery, and laboratory studies showed that factor X activity and antigen were 14% and 36% of normal, respectively. This was the first characterization of factor X deficiency at the molecular level.
De Stefano et al. (1988) reported a 13-year-old girl, born of consanguineous parents, with factor X deficiency. Laboratory studies showed normal factor X antigen levels, but the protein was severely impaired in activation via the intrinsic pathway (3% of normal) and partially defective in activation via the extrinsic pathway. The variant protein, termed factor X Roma, was activated by Russell viper venom. The parents of the proposita showed factor X functional levels compatible with heterozygosity for the abnormality. Millar et al. (2000) determined that the Roma variant results from a T318M substitution (613872.0015) in the F10 gene.
In patients with factor X deficiency from the Friuli region of Italy (Girolami et al., 1970), James et al. (1991) identified a homozygous mutation in the F10 gene (P343S; 613872.0004). Affected individuals had a moderate bleeding tendency since early childhood, with epistaxis, bleeding from the gums, posttraumatic hemarthroses, and bleeding after dental extractions and other surgical procedures. Laboratory studies showed prolonged prothrombin and partial thromboplastin clotting times, and factor X activity levels between 4 to 9% of normal. However, there was near-normal clotting times in the presence of Russell viper venom, and plasma contained normal levels of factor X antigen. Heterozygotes had intermediate levels of factor X and were usually asymptomatic.
Cooper et al. (1997) reviewed the molecular genetics of factor X and factor X deficiencies. These included CRM-negative factor X deficiency due to gene deletions and CRM-positive dysfunctional variants due to missense mutations. They tabulated 18 missense mutations.
In a study of 1,751 knockout alleles created by the International Mouse Phenotyping Consortium (IMPC), Dickinson et al. (2016) found that knockout of the mouse homolog of human F10 is homozygous-lethal (defined as absence of homozygous mice after screening of at least 28 pups before weaning).
In a patient with factor X deficiency (227600), Reddy et al. (1989) found compound heterozygosity for 2 mutations in the F10 gene: a T-to-C transition in exon 8, resulting in an arg366-to-cys (R366C) substitution in the catalytic domain, referred to as factor X San Antonio-1, and a 1-bp deletion in exon 7 (613872.0002), resulting in a frameshift at residue 272 and premature termination, referred to as factor X San Antonio-2. The patient had prolonged bleeding after surgery, and laboratory studies showed that factor X activity and antigen were 14% and 36% of normal, respectively. Reddy et al. (1989) suggested that the R366C substitution could affect the formation of a disulfide bridge and thus result in a reduction in factor X activity. This was the first characterization of factor X deficiency at the molecular level.
For discussion of the 1-bp deletion in exon 7 of the F10 gene that was found in compound heterozygous state in a patient with factor X deficiency (227600) by Reddy et al. (1989), see 613872.0001.
In a patient with factor X deficiency (227600), Watzke et al. (1990) identified a homozygous 160G-A transition in exon 2 of the F10 gene, resulting in a glu14-to-lys (E14K) substitution in the gamma-carboxyglutamic acid-rich domain. The mutation was referred to as factor X Vorarlberg. The patient was also heterozygous for a presumed E102K polymorphism in exon 5 (see 613872.0007). The mutant factor X was indistinguishable from normal on gel electrophoresis, but had only 15% residual activity in the presence of factor VIIa/tissue factor. Activation with factor IXa/VIIIa resulted in 75% activity, and activation by Russell viper venom resulted in 100% factor X activity. Further studies showed that the mutant factor X had decreased calcium affinity, which impeded a normal conformational change and resulted in a decreased rate of activation by factor VIIa/tissue factor and by factor IXa. The decrease was much more marked for the extrinsic than for the intrinsic pathway.
In patients with factor X deficiency (227600) from the Friuli region of Italy, James et al. (1991) identified a homozygous C-to-T transition in the F10 gene, resulting in a pro343-to-ser (P343S) substitution. Affected individuals had a moderate bleeding tendency since early childhood, with epistaxis, bleeding from the gums, posttraumatic hemarthroses, and bleeding after dental extractions and other surgical procedures. Laboratory studies showed prolonged prothrombin and partial thromboplastin clotting times, and factor X activity levels between 4 to 9% of normal. However, there were near-normal clotting times in the presence of Russell viper venom, and plasma contained normal levels of factor X antigen. Heterozygotes had intermediate levels of factor X and were usually asymptomatic.
In a 16-year-old girl from Santo Domingo, Dominican Republic, with severe factor X deficiency (227600), Watzke et al. (1991) identified a homozygous G-to-A transition in exon 1, resulting in an arg-to-gly substitution in the C-terminal signal sequence. This codon was referred to as codon -20, with numbering using the alanine at the NH2-terminus of the mature protein as +1. Since this amino acid occurs near the presumed cleavage site of the signal peptidase, Watzke et al. (1991) hypothesized that the mutation might prevent cleavage by the signal peptidase, which in turn would impair proper secretion of the protein. They were able to prove this hypothesis by comparing expression of wildtype and mutant factor X cDNA in a human kidney cell line. The patient had menorrhagia requiring transfusion; laboratory studies showed less than 1% factor X activity and less than 5% factor X antigen levels. The unaffected heterozygous parents had 30 to 40% factor X activity.
Racchi et al. (1993) showed that both targeting and transport of factor X Santo Domingo to the endoplasmic reticulum were functionally dissociated from the removal of the signal peptide by signal peptidase. Thus, the inability of signal peptidase to cleave factor X Santo Domingo is directly responsible for the absence of circulating factor X and leads to the bleeding diathesis in individuals with this mutation.
Marchetti et al. (1995) identified homozygosity for a ser334-to-pro (S334P) mutation in the catalytic domain of factor X in an asymptomatic subject with a CRM-positive form of factor X deficiency (227600). They also observed it in compound heterozygous state with a glu102-to-lys substitution (E102K; 613872.0007). In the 3 families studied, there were dysfunctional molecules in plasma as demonstrated by the discrepancy between clotting activity and antigen level.
For discussion of the glu102-to-lys (E102K) mutation in the F10 gene that was found in compound heterozygous state in a patient with factor X deficiency (227600) by Marchetti et al. (1995), see 613872.0006.
In affected members of a family with factor X deficiency (227600), Messier et al. (1996) identified a heterozygous 964G-A transition in the F10 gene, resulting in an asp282-to-asn (D282N) substitution. The patients had a history of bleeding after surgery, including tonsillectomy, appendectomy, removal of basal cell tumor, hysterectomy, after dental work, and in association with childbirth, menses, and injuries. In addition, there were prolonged nosebleeds and easy bruising. All 14 affected members in 3 generations were heterozygotes. One of the authors worked in Stockton, California, where presumably at least some of the family members lived. Millar et al. (2000) found that an affected member of the kindred reported by Messier et al. (1996) was a compound heterozygote for the asp282-to-asn mutation and an arg287-to-trp (613872.0014) substitution, thus confirming autosomal recessive transmission of the disorder.
Rudolph et al. (1996) screened commercially available plasma and identified a variant with normal factor X antigen but less than 1% factor X activity by a prothrombin time-based clotting assay. These findings were consistent with factor X deficiency (227600). A 1200A-G transition in exon 2 of the F10 gene resulted in a glu7-to-gly (E7G) substitution, which was referred to as factor X St. Louis-2. The donor was apparently homozygous for the defect. Other substitutions for glu in factor X resulting in a mild bleeding tendency are described in 613872.0003 and 613872.0010.
In a patient with deficient factor X activity (227600), Kim et al. (1995) identified a 206A-to-G transition in exon 2 of the F10 gene, resulting in a glu14-to-gly (E14G) substitution, which was referred to as factor X Ketchikan. This mutation deleted a gamma-carboxylated glutamic acid normally produced by posttranslational gamma-carboxylation of the glu at position 14. Kim et al. (1995) considered the patient to be homozygous for the defect, but the possibility of a simultaneous occurrence of an undetected deletion in one of the factor X genes was not explored. The patient's parents were not known to be consanguineous. The defect could explain the decreased functional activity of circulating factor X and the mild bleeding tendency of the patient.
In 2 brothers with factor X deficiency (227600), Zama et al. (1999) identified a homozygous G-to-C transversion in the F10 gene, resulting in a glu32-to-gln (E32Q) substitution, which was referred to as factor X Tokyo. Residue 32 normally undergoes gamma-carboxylation within the gamma-carboxyglutamic acid rich domain. Both parents of the brothers were heterozygotes; both daughters of one of the affected brothers were heterozygotes.
In a father and 2 children with moderate bleeding (hematoma), epistaxis, and moderate uterine bleeding, respectively, Millar et al. (2000) demonstrated heterozygosity for a G-to-C transversion in the last base of exon 7, predicted to result in a gly249-to-arg (G249R) substitution. However, this deletion could in principle affect splicing, since (1) a guanine residue at position -1 was found to be present in 77% of donor splice sites analyzed by Padgett et al. (1986), and (2) there were 21 other examples of such G-to-C substitutions causing human genetic disease listed in the Human Gene Mutation Database (Cooper et al., 1998). Millar et al. (2000) thus proposed that a resultant truncated protein may exert a dominant-negative effect by binding competitively to molecules and denying access of the wildtype allele to such sites.
In the proband of a family with factor X deficiency (227600) reported by Cooper et al. (1997), Millar et al. (2000) identified compound heterozygosity for 2 mutations in the F10 gene: a G-to-A transition resulting in a val298-to-met (V298M) substitution, and an intragenic deletion resulting in a truncated protein.
Millar et al. (2000) found that an affected member of the kindred with factor X deficiency (227600) reported by Messier et al. (1996) was a compound heterozygote for an arg287-to-trp (R287W) substitution in the F10 gene and an asp282-to-asn (D282N; 613872.0008) substitution.
De Stefano et al. (1988) reported a 13-year-old girl, born of consanguineous parents, with factor X deficiency (227600). Laboratory studies showed normal factor X antigen levels, but the protein was severely impaired in activation via the intrinsic pathway (3% of normal) and partially defective in activation via the extrinsic pathway. The variant protein, termed factor X Roma, was activated by Russell viper venom. The parents of the proposita showed factor X functional levels compatible with heterozygosity for the abnormality. Millar et al. (2000) determined that the Roma variant results from a T318M substitution in the F10 gene.
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