Alternative titles; symbols
HGNC Approved Gene Symbol: F9
SNOMEDCT: 41788008, 767712006; ICD10CM: D67; ICD9CM: 286.1;
Cytogenetic location: Xq27.1 Genomic coordinates (GRCh38): X:139,530,739-139,563,459 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xq27.1 | {Deep venous thrombosis, protection against} | 300807 | X-linked recessive | 3 |
| {Warfarin sensitivity} | 301052 | X-linked | 3 | |
| Hemophilia B | 306900 | X-linked recessive | 3 | |
| Thrombophilia 8, X-linked, due to factor IX defect | 300807 | X-linked recessive | 3 |
The F9 gene encodes coagulation factor IX, which circulates as an inactive zymogen until proteolytic release of its activation peptide allows it to assume the conformation of an active serine protease (Davie and Fujikawa, 1975). Its role in the blood coagulation cascade is to activate factor X (F10; 227600) through interactions with calcium, membrane phospholipids, and factor VIII (F8; 300841). Factor IX and factor X both consist of 2 polypeptide chains referred to as the L (light) and H (heavy) chains. The H chain bears a structural resemblance to the polypeptide chain of the pancreatic serine protease trypsin (PRSS1; 276000). The L chain is covalently linked to the H chain by a single disulfide bond (Fujikawa et al., 1974).
Kurachi and Davie (1982) isolated and characterized a cDNA coding for the human factor IX gene. The deduced 416-residue protein contains a 46-residue leader sequence that includes both a signal sequence and a pro-sequence for the mature protein that circulates in plasma. The amino-terminal region contains 12 glutamic acid residues that are converted to gamma-carboxyglutamic acid in the mature protein. The arginyl peptide bonds that are cleaved in the conversion of human factor IX to factor IXa by factor XIa (F11; 264900) were identified as Arg145-Ala146 and Arg180-Val181. The cleavage of these 2 internal peptide bonds results in the formation of a 35-residue activation peptide and factor IXa, a serine protease composed of a 145-residue light chain and a 236-residue heavy chain that are held together by a disulfide bond. The homology in the amino acid sequence between human and bovine factor IX was found to be 83%.
Choo et al. (1982) isolated clones corresponding to the human factor IX gene from a human cDNA library. The deduced human protein showed 78% homology with the bovine protein.
Jagadeeswaran et al. (1984) used the peptide sequence of bovine F9 to develop a probe to screen a human liver cDNA library. They identified a recombinant clone corresponding to 70% of the coding region of human factor IX. This F9 cDNA was used to probe restriction endonuclease digested polymorphism, as well as to verify that the haploid genome contains a single copy of the gene.
Anson et al. (1984) isolated clones corresponding to the full sequence of the human factor IX gene from a human liver cDNA library. The gene encodes a mature 415-residue protein.
Anson et al. (1984) determined that the F9 gene contains 8 exons and spans about 34 kb. Introns accounted for 92% of the gene length. Exons conformed roughly to previously designated protein regions but the catalytic region of the protein appeared to be coded by 2 separate exons, which differed from the arrangement in other characterized serine protease genes.
Factor IXa activates factor X as part of an intrinsic activating complex that also consists of factor VIIIa. Using several chimeric and mutant F9 proteins in coagulation assays, Wilkinson et al. (2002) determined that residues 88 to 109, excluding arg94, within the second epidermal growth factor-like domain of factor IX are important for phospholipid surface assembly of the factor X activating complex.
Rusconi et al. (2002) demonstrated that protein-binding oligonucleotides (aptamers) against coagulation factor IXa are potent anticoagulants. They also showed that oligonucleotides complementary to these aptamers could act as antidotes capable of efficiently reversing the activity of these new anticoagulants in plasma from healthy volunteers and from patients who cannot tolerate heparin. Rusconi et al. (2002) concluded that their strategy was generalizable for rationally designing a drug-antidote pair, thus opening the way for developing safer regulatable therapeutics.
Camerino et al. (1983) used a factor IX gene probe to demonstrate close linkage to the locus for fragile X syndrome (300624) (17 nonrecombinants, 0 recombinants; lod = 5.12 at theta = 0.0).
Chance et al. (1983) assigned the human F9 gene to chromosome Xq27-qter using somatic cell hybridization. F9 was in a fragment of the X chromosome associated with no HPRT (308000) activity in the hybrid cell, suggesting that F9 is distal to HPRT.
Using a cDNA probe in the study of human-mouse hybrid cells, Camerino et al. (1984) mapped the F9 locus to Xq26-q27. Furthermore, they identified a TaqI polymorphism with allelic frequencies of about 0.71 and 0.29. By in situ hybridization and by study of rodent-human somatic cell hybrids with various aberrations of the human X, Boyd et al. (1984) assigned the factor IX locus to Xq26-qter. Jagadeeswaran et al. (1984) also mapped the F9 gene to Xq26-qter.
Hemophilia B
Using genomic DNA probes, Chen et al. (1985) identified a partial intragenic deletion in the F9 gene in 7 affected members of a family with severe hemophilia B (306900).
In affected members of a family with severe factor IX deficiency and no detectable factor IX protein, Taylor et al. (1988) identified a complete deletion of the F9 gene that extended at least 80 kb 3-prime of the gene. The proband did not have antibodies to factor IX, despite total deletion of the gene.
Matthews et al. (1988) discussed the family originally reported by Peake et al. (1984) as having an X-chromosome deletion of minimum size 114 kb that included the entire F9 gene. By isolation of further 3-prime flanking probes, they located the 3-prime breakpoint of the deletion to a position 145 kb 3-prime to the start of the F9 gene. Abnormal junction fragments detected at the breakpoint were used in the detection of carriers.
In a patient with severe hemophilia B, Siguret et al. (1988) found loss of the TaqI restriction site at the 5-prime end of exon 8 of the F9 gene. Using oligonucleotide probes and PCR-amplified DNA for sequencing of the affected region, the authors identified a C-to-T change in the catalytic domain of the protein, resulting in premature termination. The change resulted from a CpG mutation.
By use of PCR followed by sequencing, Bottema et al. (1989) identified mutations in the F9 gene (see, e.g., 300746.0051) in all 14 hemophilia B patients studied. Analysis for heterozygosity in at-risk female relatives was then done, either by sequencing the appropriate region or by detection of an altered restriction site.
Green et al. (1991) provided a list of point mutations that cause hemophilia B. Sommer et al. (1992) estimated that missense mutations cause only 59% of moderate and severe hemophilia B and that these mutations are almost always (95%) of independent origin (i.e., de novo mutations). In contrast, missense mutations were found in virtually all (97%) families with mild disease and only a minority of these (41%) were of independent origin.
Giannelli et al. (1993) reported on the findings in a database of 806 patients with hemophilia B in whom the defect in factor IX had been identified at the molecular level. A total of 379 independent mutations were described. The list included 234 different amino acid substitutions. There were 13 promoter mutations, 18 mutations in donor splice sites, 15 mutations in acceptor splice sites, and 4 mutations creating cryptic splice sites. In analyses of DNA from 290 families with hemophilia B (203 independent mutations), Ketterling et al. (1994) found 12 deletions more than 20 bp long. Eleven of these were more than 2 kb long and one was 1.1 kb.
Giannelli et al. (1996) described the sixth edition of their hemophilia B database of point mutations and short (less than 30 bp) additions and deletions. The 1,380 patient entries were ordered by the nucleotide number of their mutation. References to published mutations were given and the laboratories generating the data were indicated. Giannelli et al. (1997) described the seventh edition of their database; 1,535 patient entries were ordered by the nucleotide number of their mutation. When known, details were given on factor IX activity, factor IX antigen in the circulation, presence of inhibitor, and origin of mutation.
Ljung et al. (2001) surveyed a series comprising all 77 known families with hemophilia B in Sweden. The disorder was severe in 38, moderate in 10, and mild in 29. A total of 51 different mutations were found. Ten of the mutations, all C-to-T or G-to-A transitions, recurred in 1 to 6 additional families. Using haplotype analysis of 7 polymorphisms in the F9 gene, Ljung et al. (2001) found that the 77 families carried 65 unique, independent mutations. Of the 48 families with severe or moderate hemophilia, 23 (48%) had a sporadic case compared with 31 families of 78 (40%) in the whole series. Five of those 23 sporadic cases carried de novo mutations; 11 of 23 of the mothers were proven carriers; and in the remaining 7 families, it was not possible to determine carriership.
X-Linked Thrombophilia due to Factor IX Defect
In an Italian man with deep venous thrombosis of the femoral-popliteal veins (THPH8; 300807), Simioni et al. (2009) identified a hemizygous mutation in the F9 gene (R338L; 300746.0112). Coagulation studies showed that he had normal levels of F9 antigen, but very high levels of F9 activity (776% of control values).
Warfarin Sensitivity
In a 49-year-old patient who was found to have warfarin sensitivity, Chu et al. (1996) identified an A-10T mutation in the propeptide of the factor IX gene (A37T; 300746.0102). The mutation was found by direct sequence analysis of amplified genomic DNA from all 8 exons and exon-intron junctions of F9.
In 3 patients with warfarin sensitivity, Oldenburg et al. (1997) identified mutations in the F9 gene: A-10T in 1 patient and an A-10V mutation (A37V; 300746.0103) in the others.
Pezeshkpoor et al. (2018) identified the A37T mutation in the F9 gene in 11 patients with X-linked warfarin sensitivity, including 6 patients previously reported by Oldenburg et al. (2001), and the A37V mutation in 7 patients, including 5 patients previously reported by Oldenburg et al. (2001). Expression of F9 containing the A37T mutation or the A37V mutation in HEK293T cells resulted in a reduction in the FIX:C ratio and a reduced half maximal inhibitory concentration (IC50) for warfarin compared to HEK293T cells transfected with wildtype F9. This indicated a sensitivity to warfarin conferred by both mutations, with A37V conferring less warfarin sensitivity than A37T.
By haplotype analysis in 11 patients with the A37T mutation and 7 patients with the A37V mutation, Pezeshkpoor et al. (2018) found that both were founder mutations in the European population. They noted that 2 patients from the US with the A37T mutation (patients J and K in Oldenburg et al., 2001) shared a different haplotype than the 9 European patients with the A37T mutation, indicating an independent origin.
Mechanism of Mutation Generation
Methylation of CpG dinucleotides constitutes an endogenous mechanism of mutation, which results from insufficient repair of the deamination product to 5-methyl cytosine (Ketterling et al., 1993). Among 22 patients with hemophilia B, Koeberl et al. (1989) found a high rate of mutation at CpG dinucleotides. Transitions of CpG accounted for 31% (5 out of 16) of distinct mutations and for 38% (5 out of 13) of single base changes. The authors used a method of genome amplification with transcript sequencing to perform direct sequencing on 8 regions of the F9 gene.
Cooper and Krawczak (1990) made an extensive survey of single basepair substitutions that cause various human genetic diseases and found that 32% were CG-to-TG or CG-to-CA transitions. This was a 12-fold increase over the frequency predicted from random expectation. They presented a computer model (MUTPRED) designed to predict the location of mutations within gene coding regions causing human genetic disease. The model predicted successfully the rank order of disease prevalence and/or mutation rates associated with various human autosomal dominant and X-linked recessive conditions. The mutational spectrum predicted for the F9 gene resembled closely that observed for point mutations causing hemophilia B. Cooper and Krawczak (1990) quoted from Edmund Spenser's 'The Faerie Queene' (circa 1609): '...mutability in them doth play her cruell cruell sports, to many men's decay.'
To study the nature of spontaneous mutation, Koeberl et al. (1990) sequenced 8 regions (a total of 2.46 kb) of likely functional significance in the F9 gene in 60 consecutive, unrelated patients with hemophilia B. From the pattern of mutations causing disease and from a knowledge of evolutionarily conserved amino acids, they reconstructed the underlying pattern of mutation and calculated the mutation rates per basepair per generation for transitions (G-A or C-T changes) as 27 x 10(-10), transversions (A-T, A-C, G-T, or G-C changes) as 4.1 x 10(-10), and deletions as 0.9 x 10(-10), for a total mutation rate of 32 x 10(-10). No insertions were observed in this sample. The proportion of transitions at non-CpG dinucleotides was raised 7-fold over that expected if 1 base substitution were as likely as another; at the dinucleotide CpG, transitions were found to be increased 24-fold relative to transitions at other sites. Mutations putatively affecting splicing accounted for at least 13% of mutations, indicating that the division of the gene into 8 exons represents a significant genetic cost to the organism. All the missense mutations occurred at evolutionarily conserved amino acids.
Bottema et al. (1990) found that in Asians (mostly Koreans), as in Caucasians, transitions dominate among F9 mutations, followed by transversions and microdeletions/insertions. On the basis of their data combined with previous data, the authors concluded that more than two-thirds of the missense mutations that can occur at nonconserved amino acids do not cause hemophilia B.
In their series of patients with hemophilia B, Chen et al. (1991) found that 23 (45%) of 51 substitutions in the F9 gene occurred as C-to-T or G-to-A transitions at 11 sites within CpG dinucleotides. More than 1 family had identical defects for 6 of the CpG mutations. At 4 of these sites, most patients had different haplotypes compatible with distinct mutations. Non-CpG mutations occurred throughout the coding regions with only 1 mutation in more than one family.
Bottema et al. (1991) identified 95 independent missense mutations in the F9 gene resulting in hemophilia B; 94 of these occurred at amino acids that are evolutionarily conserved in mammalian factor IX sequences. They pointed out that the likelihood of a missense mutation causing hemophilia B depends on whether the residue is also conserved in the factor IX-related proteases: factor VII, factor X (F10; see 227600), and protein C (PROC; 612283). They found that most of the possible missense mutations in residues conserved in factor IX in all the related proteases resulted in disease, whereas missense mutations not conserved in the related proteases were 6-fold less likely to cause disease. Missense mutations at nonconserved residues were 33-fold less likely to cause disease. Bottema et al. (1991) concluded that many of the residues in factor IX are spacers; that is, the main chains are presumably necessary to keep other amino acid interactions in register, but the nature of the side chain is unimportant.
Bottema et al. (1991) found that transversions at CpG dinucleotides are elevated an estimated 7.7-fold relative to other transversions. On the other hand, the mutation rates at non-CpG dinucleotides are relatively uniform. They suggested that the high rate of CpG transversions accounts for the fact that the F9 gene has a G+C content of approximately 40%.
Bottema et al. (1993) gave an updated estimate on mutations at CpG dinucleotides in the F9 gene. Of the independent transitions they had delineated in a consecutive sample of 290 families with hemophilia B, 42% occurred at CpG sites. Overall, CpG mutations represented 36% of the point mutations and 30% of all mutations in their sample. An observed 20-fold enhancement for mutation at CpG sites with frequent mutations reflected, they suggested, the situation at fully or mostly methylated sites.
Based particularly on his extensive experience with mutation analysis in hemophilia B, Sommer (1994) proposed an ingenious hypothesis concerning the role of cancer in mediating evolutionary selection for a constant rate of germline mutation. The hypothesis was based on data suggesting that most germline mutations are due to endogenous processes such as methylation of DNA at CpG dinucleotides. Furthermore, despite differences in environment, diet, lifestyle, and occupational exposure, the pattern of factor IX mutations is remarkably similar in populations all over the world. Also despite the many differences in the environment of modern day humans, the biases in the dinucleotide mutation rates during the past 150 years are compatible with the ancient pattern that fashioned the G+C content of 40%. Assuming that somatic mutation leading to early-onset cancer occurs at rates similar to the germline mutation rate, then these cancers that interfere with reproduction might cap the germline mutation rate. Some have pointed out that cancer is a sensitive mediator of negative selection because the multiple mutations required for carcinogenesis can amplify the effects of small increases in the mutation rate. A certain rate of mutation is required to generate sufficient variation for adaptation during evolutionary time. Sexual reproduction and recombination serves to enhance variation, but ultimately new germline mutation is required to replenish variant alleles lost secondary to negative selection, genetic drift, and population bottlenecks. Unfortunately, the requisite mutation rate carries a terrible price, since for each advantageous mutation, there are many disadvantageous ones. Consequently, the optimal mutation rate should be at a level just sufficient to maintain the variation needed for adaptation. Mechanisms for negative selection are needed to keep the mutation rate in check. Cancer may serve that role.
Of 727 independent mutations (0.28%) of the F9 gene in patients with hemophilia B, Li et al. (2001) observed only 2 germline retrotransposition mutations: a 279-bp insertion in exon 8 originating from an Alu family of short interspersed elements not previously known to be active, and a 463-bp insertion in exon e of a LINE-1 element originating in a maternal grandmother. The authors stated that if the rates of recent germline mutation in F9 are typical of the genome, a retrotransposition event is estimated to occur somewhere in the genome of about 1 in every 17 children born. Analysis of other estimates for retrotransposition frequency and overall mutation rates suggested that the actual rate of retrotransposition is likely to be in the range of 1 in every 2.4 to 1 in every 28 live births. Kazazian (1999) analyzed the frequency of retrotransposition events involving 860 genes. These included retrotranspositions identified in X-linked and severe autosomal dominant disorders, likely to have occurred within the last 150 years, and autosomal recessive disorders in which the mutations may have occurred 10,000 or more years ago.
Hirosawa et al. (1990) noted that all 5 families with hemophilia B Leyden, in which a severe bleeding disorder in childhood becomes mild after puberty, had mutations in an approximately 40-kb region in the 5-prime untranslated region of F9, which the authors referred to as the Leyden-specific region (LSR). Base changes at nucleotide -20 (300746.0001) as well as at nucleotide -6 (300746.0002) and deletions of the 3-prime half of the LS region reduced expression of the factor IX gene to about 15-31% that of normal controls, as assessed in a cultured cell (HepG2) expression system. Androgen significantly increased the transcriptional activities of both mutant and normal factor IX genes in a concentration-dependent manner. The findings suggested that a mutations in this region could lead to a switch from constitutive to steroid hormone-dependent gene expression.
Kurachi et al. (2009) stated that the LSR has been narrowed to an approximately 50-bp region between nucleotides -34 and +19. Crossley and Brownlee (1990) identified a binding site for the CCAAT/enhancer binding protein (C/EBP, CEBPA; 116897) extending from +1 to +18 in the F9 gene, which is capable of transactivating a factor IX promoter. Hepatocyte nuclear factor-4 (HNF4; 600281), a member of the steroid hormone receptor superfamily of transcription factors, also binds to nucleotides -26 to -20 of the promoter region in the F9 gene (Reijnen et al., 1992).
Kundu et al. (1998) generated a transgenic mouse model of hemophilia B by targeted disruption of the murine F9 gene. The tail bleeding time of hemizygous male mice was markedly prolonged compared with those of normal and carrier female littermates. Seven of 19 affected male mice died of exsanguination after tail snipping, and 2 affected mice died of umbilical cord bleeding. Ten affected mice survived to 4 months of age. Aside from the factor IX defect, carrier female and hemizygous male mice had no liver pathology by histologic examination, were fertile, and transmitted the mutation in the expected mendelian frequency.
Gu et al. (1999) found factor IX deficiency in 2 distinct dog breeds. In 1 breed, the disorder was associated with a large deletion mutation, spanning the entire 5-prime region of the F9 gene extending to exon 6. In the second breed, an insertion of approximately 5 kb disrupted exon 8. The insertion was associated with alternative splicing between a donor site 5-prime and acceptor site 3-prime to the normal exon 8 splice junction, with introduction of a new stop codon.
Brooks et al. (2003) found that mild hemophilia B in a large pedigree of German wirehaired pointers was caused by a line-1 insertion in the factor IX gene. The insertion could be traced through at least 5 generations and segregated with the hemophilia B phenotype.
Blood coagulation capacity increases with age in healthy individuals. Through extensive longitudinal analyses of human factor IX gene expression in transgenic mice, Kurachi et al. (1999) identified 2 essential age regulatory elements that they termed AE5-prime and AE3-prime. These elements are required and together are sufficient for normal age regulation of factor IX expression. AE5-prime, located between nucleotides -770 through -802, is a PEA3-related element present in the 5-prime upstream region of the gene encoding factor IX and is responsible for age-stable expression of the gene. AE3-prime, located in the middle of the 3-prime untranslated region, is responsible for age-associated elevation in mRNA levels. In a concerted manner, AE5-prime and AE3-prime recapitulate natural patterns of the advancing age-associated increase in factor IX gene expression.
In transgenic mice with hemophilia B Leyden (-20T-A; 300746.0001), which usually show amelioration of the disorder after puberty, Kurachi et al. (2009) found that expression of different F9 minigenes with or without the age-related stability element (ASE) in the 5-prime untranslated region resulted in different disease course. Mice with no ASE failed to show the Leyden phenotype, showing only transient F9 expression at puberty, whereas mice with ASE showed normal pubertal F9 recovery. These changes were not sex-dependent, indicating that testosterone and androgen are not responsible. Further studies showed that the transcription factor Ets1 (164720) was the specific ASE-binding protein responsible for its activation and F9 gene expression. In addition, F9 expression was abolished by hypophysectomy, but restored with growth hormone (GH; 139250) administration in both males and females. These results provided a molecular mechanism for the puberty-related Leyden phenotype. Kurachi et al. (2009) also generated transgenic mice expressing the Brandenberg F9 mutation (-26G-C; 300746.0097), which showed a severe phenotype without amelioration after puberty.
Veltkamp et al. (1970) described a variant of hemophilia B, termed hemophilia B Leyden (see 306900), in a Dutch family. The disorder was characterized by the disappearance of the bleeding diathesis as the patient aged. In affected individuals, plasma factor IX levels were less than 1% of normal before puberty, but after puberty factor IX activity and antigen levels rose steadily in a 1:1 ratio to a maximum of 50 to 60%. Briet et al. (1982) described a similar variant of hemophilia B that took a severe form early in life but remitted after puberty, with an increase in factor IX levels from below 1% of normal to about 50% of normal by age 80 years. Three pedigrees with 27 affected males with this disorder could be traced to a small village in the east of the Netherlands. In affected members of 2 Dutch pedigrees with hemophilia B Leyden, Reitsma et al. (1988) found that patients with hemophilia B Leyden had a T-to-A transversion in the promoter region of the F9 gene at position -20. The findings suggested that a point mutation in this region could lead to a switch from constitutive to steroid hormone-dependent gene expression.
Reijnen et al. (1992) demonstrated that the -20 promoter mutation disrupts the binding of hepatocyte nuclear factor-4 (HNF4; 600281), a member of the steroid hormone receptor superfamily of transcription factors. Studies also demonstrated that the G-to-C mutation at -26 (300746.0097) also disrupts the binding of HNF4. Whereas HNF4 transactivated the wildtype promoter sequence in liver and nonliver (e.g., HeLa) cell types, it transactivated the -20 mutated promoter to only a limited extent and the -26 mutated promoter not at all. The data suggested that HNF4 is a major factor controlling factor IX expression in the normal individual. Furthermore, the severity of the hemophilia phenotype appeared to be related directly to the degree of disruption of HNF4 binding and transactivation; the -26 G-to-C mutation was accompanied by a bleeding tendency did not ameliorate after puberty.
Fahner et al. (1988) found a G-to-A change at nucleotide -6 as the cause of hemophilia B Leyden (see 306900), in which a severe bleeding disorder in childhood becomes mild after puberty.
Crossley et al. (1990) also identified a G-to-A change at position -6 as the cause of hemophilia B Leyden.
Attree et al. (1989) found a G-to-C change at nucleotide -6. Vidaud et al. (1993) cited evidence indicating that the G-C transversion at position -6 produces much milder hemophilia B Leyden (see 306900) than does the G-A transition at the same position (300746.0002).
Reitsma et al. (1989) studied the F9 gene in a Greek patient and an American patient of Armenian descent with hemophilia B Leyden (see 306900). In one they found deletion of A at position +13 of the factor IX gene and in the other an A-to-G mutation at the same position (300746.0090), 32 bp downstream of the point mutation in the Dutch kindred (Reitsma et al., 1988). See also Crossley et al. (1989). Crossley and Brownlee (1990) identified a binding site for the CCAAT/enhancer binding protein (C/EBP) extending from +1 to +18. They showed that the A-to-G mutation at +13 prevents the binding of C/EBP to this site. Furthermore, they showed that C/EBP is capable of transactivating a cotransfected normal factor IX promoter but not the mutant promoter.
Koeberl et al. (1989) described a normal variant, isoleucine or phenylalanine, at position -40 in exon 1 of the F9 gene.
Tanimoto et al. (1988) found a normal polymorphism, A to G, at nucleotide 192 in IVS1 of the F9 gene.
In a review of known factor IX mutations from all hemophilia B (306900) patients registered at the Malmo hemophilia center in Sweden and from the entire UK hemophilia population, Green et al. (1992) noted that 4 of 7 arg-4trp (R-4W) mutations, resulting from a 6364C-T transition, occurred on different haplotypes, indicating that they were independent mutations.
This variant has been called factor IX San Dimas and factor IX Kawachinagano.
In a case (designated Ox3) of severe hemophilia B (306900) of the CRM-positive type, Bentley et al. (1986) of Oxford University found mutation of arginine to glutamine at position -4, leading to defective cleavage of the N-terminal propeptide. The type of mutation in this mutant factor IX is similar to that in the procollagen molecule (either the alpha-1 or alpha-2 chain of type I collagen) in cases of type VII Ehlers-Danlos syndrome. Two proteolytic cleavages normally occur to remove the prepeptide and the propeptide regions. The mutant F9 had 18 additional amino acids on the N-terminal portion. Normally the signal peptidase cleaves the peptide bond between residues -18 and -19. Further cleavage to mature F9 depends on the arginine residue at -4. Arginine at -4 shows evolutionary conservation in factor X, prothrombin, C3, C4, C5, and tissue type plasminogen activator--all proteins that, like F9, are processed by site-specific trypsin-like enzymes. In addition to the CRM-positive and CRM-negative forms, there is a CRM-reduced class. Sugimoto et al. (1989) demonstrated by amino acid sequence that the mutant factor IX retained the propeptide region of 18 amino acids due to a substitution of arginine at position -4 by glutamine. They assumed that this attached propeptide region of the molecule directly interferes with the adjacent NH(2)-terminus and prevents the metal-induced conformational changes that are essential for biologic activity of normal factor IX.
Ware et al. (1989) studied the intragenic defect in factor IX San Dimas, which was derived from a patient with moderately severe hemophilia B (306900) who had 98% factor IX antigen but very low factor IX clotting activity. They found that a G-to-A transition in exon 2 of the F9 gene resulted in the substitution of a glutamine for an arginine codon -4 in the propeptide of factor IX. The variant protein circulated in the plasma as profactor IX with a mutant 18-amino acid propeptide still attached. Factor IX San Dimas shows similarities to factor IX Cambridge, which has a substitution of serine for arginine at -1 (300746.0009).
Factor IX Kawachinagano is a mutant factor IX protein initially recognized in a patient with severe hemophilia B who had 46% of normal factor IX antigen but no detectable clotting activity. This mutant factor IX is not activated by factor XIa in the presence of calcium ions. Sugimoto et al. (1989) determined that factor IX Kawachinagano results from an arg-to-gln substitution at the -4 position of the F9 gene. The substitution resulted in impaired function of the Gla-domain caused by an attached propeptide region.
Diuguid et al. (1986) found that mutant factor IX Cambridge, isolated from a patient with severe hemophilia B (306900), has an 18-residue propeptide attached to its NH2-end. A point mutation at residue -1, from arginine to serine, precluded cleavage of the propeptide by the processing protease and interfered also with gamma-carboxylation of the mutant factor IX. The last effect indicates the importance of the leader sequence in substrate recognition by the vitamin K-dependent carboxylase.
See Winship (1989).
See Winship (1989); the patient studied had a severe form of hemophilia B (306900).
Information was provided by Bertina (1989); the patient studied had a severe form of hemophilia B (306900).
This variant has been designated factor IX Seattle-3.
Chen et al. (1989) studied 5 patients with severe hemophilia B (306900) and detectable factor IX antigen that showed altered reactivity to a specific polyclonal antibody fraction or monoclonal anti-factor IX antibody. By the PCR technique, they identified a single base transition in each of the 5 families. Three different mutations were identified: factor IX Seattle-3 showed a G-to-A transition in exon 2, changing the codon for glu27 to lys; factor IX Durham showed a G-to-A transition in exon 4, changing the codon for gly60 to ser; and factor IX Seattle-4 showed a G-to-A transition in exon 8, changing arg248 to gln in exon 8.
This variant has been designated factor IX Chongqing.
Wang et al. (1990) studied a Chinese patient with sporadic hemophilia B (306900) of severe form. A defect in the factor IX Gla domain was suspected because of low antigen on an assay using a calcium-dependent antibody fraction. Since the Gla domain is coded mainly by exon 2, Wang et al. (1990) amplified and sequenced the exon and found an A-to-T substitution at nucleotide 6455. The transversion changed glutamic acid-27 to valine. In leukocyte DNA from the patient's mother, the nucleotide sequence of exon 2 was entirely normal.
See Green et al. (1989). This mutation, which is due to a transition at a CpG dinucleotide, was found by Koeberl et al. (1990) in 2 cases of severe hemophilia B (306900). Koeberl et al. (1990) estimated that approximately 1 in 4 individuals with hemophilia B can be expected to have a mutation at arginine and concluded that nonsense mutations at 1 of the 6 arginine residues are common causes of severe hemophilia.
See Koeberl et al. (1989) and Zhang et al. (1989). The hemophilia (306900) was clinically mild.
See Koeberl et al. (1989).
Brownlee (1988) described a GT-to-GG donor splice site mutation in IVS3 in association with severe hemophilia B (306900).
Davis et al. (1984, 1987) found that factor IX Alabama, a CRM+ mutation responsible for a clinically moderate form of hemophilia B (306900), has an adenine to guanine transition in the first nucleotide of exon d, causing substitution of glycine for aspartic acid (GAT to GGT) at residue 47. The structural defect in factor IX Alabama results in a molecule with 10% of normal coagulant activity. McCord et al. (1990) concluded that the asp47-to-gly mutation, which occurs in a calcium-binding site, results in a loss of a stable calcium-mediated conformational change, leading to improper interaction with factor VIIIa and factor X.
See Lozier et al. (1989). The hemophilia (306900) was clinically severe.
This variant has been designated factor IX Hollywood.
See Green et al. (1989) and Spitzer et al. (1989). The hemophilia (306900) was clinically mild.
This variant has been designated factor IX Durham.
In 2 men with mild hemophilia B (306900), Denton et al. (1988) found that the highly conserved gly60 residue had been changed to ser. The mutation was accompanied by defective epitope expression in the 2 patients, suggesting that a change in the tertiary structure of the EGF-like domain is the cause of the mild hemophilia B. See Chen et al. (1989).
Poort et al. (1989) found the same mutation in a Dutch family. A G-to-A change at position 10430 in exon 4 was responsible. The presence of the same mutation in 3 patients from distinct geographic areas confirmed the notion that CpG dinucleotides are 'hotspots' for mutation.
See Green et al. (1989). The hemophilia (306900) was clinically mild.
See Winship et al. (1989). The hemophilia (306900) was clinically severe.
See Green et al. (1989). The hemophilia (306900) was clinically severe.
Liddell et al. (1989) described a molecular defect in factor IX Cardiff, a variant that showed faulty activation with the production of a stable reaction product with a molecular weight compatible with that of a putative light chain-activation intermediate. A single C-to-T transition was discovered that changed the arg residue at position 145 (the first residue of the first bond in the activation peptide) to a cys. The hemophilia (306900) was clinically moderate to severe.
Factor IX Chapel Hill, a CRM+ variant of mild hemophilia B (306900), results from an arg-to-his change at residue 145, which prevents cleavage at one of the activation sites (Noyes et al., 1983). See Koeberl et al. (1989). Suehiro et al. (1990) concluded that the arg145-to-his substitution impairs the cleavage between the light chain and the activation peptide by factor XIa/calcium ions.
This variant has also been called factor IX Nagoya-3.
McGraw et al. (1985) identified a common polymorphism at the third amino acid residue in the activation peptide of the F9 gene: an A-to-G transition resulting in a thr148-to-ala (T148A) substitution.
Winship and Brownlee (1986) also identified the 20422A-G transition in the F9 gene and found that it gave rise to an MnlI RFLP. However, technical problems made it difficult to detect the polymorphic fragments by conventional Southern blotting. The polymorphism as identified by oligonucleotide probes was used for linkage studies in a 3-generation family.
Graham et al. (1988) showed that the F9 protein with thr148 reacted to the mouse monoclonal antibody, whereas that with ala148 did not. The polymorphism is referred to as the F9 Malmo polymorphism; positive reactors are designated Malmo A, and negative reactors are designated Malmo B. Strong linkage disequilibrium was found with 2 other intragenic RFLPs.
Bezemer et al. (2008) reported that the G allele (ala148) of F9 Malmo (rs6048) was associated with a 15 to 43% decrease in deep vein thrombosis risk compared to the A allele in 3 case-control studies of deep vein thrombosis. This common variant has a minor allele frequency of 0.32. The substitution occurs in the portion of the factor IX zymogen that is cleaved from the zymogen to activate factor IX. The authors noted that this variant had not been reported to be associated with hemophilia B (306900). In a follow-up study from 3 case-control studies involving a total of 1,445 male patients with deep venous thrombosis and 2,351 male controls, Bezemer et al. (2009) found that the G allele of F9 Malmo conferred protection against deep venous thrombosis (odds ratio of 0.80); see 300807. The pooled corresponding odds ratio in a comparable number of women with deep venous thrombosis was 0.89. However, factor IX antigen level, factor IX activation peptide levels, and endogenous thrombin potential did not differ between the F9 Malmo genotypes. Although F9 Malmo was the most strongly associated with protection from deep vein thrombosis, the biologic mechanism remained unknown.
See Koeberl et al. (1989). The hemophilia (306900) was clinically severe.
This variant has been called factor IX B(M) Nagoya and factor IX Deventer.
Suehiro et al. (1989) demonstrated substitution of tryptophan for arginine at position 180 in the factor IX protein of a patient with severe hemophilia B (306900). Bertina et al. (1990) found the same mutation.
This variant has been called factor IX Hilo and factor IX Novara.
A subset of hemophilia B patients have a prolonged prothrombin time (PT) when exposed to bovine (or ox) brain tissue; these CRM+ patients are classified as having hemophilia B(M) (see 306900). Huang et al. (1989) demonstrated a point mutation in a hemophilia B(M) variant, factor IX Hilo. Glutamine (CAG) was substituted for arginine (CGG) at amino acid 180 in exon 6 (G-to-A at nucleotide 20519). Bertina et al. (1990) found the same mutation. The hemophilia was clinically severe.
Lefkowitz et al. (1993) noted that the bovine brain tissue in studies of hemophilia B(M) is the source of thromboplastin, or tissue factor (F3; 134390); PT times determined with thromboplastin from rabbit brain or human brain are not reported to be prolonged. However, in various studies of factor IX Hilo, Lefkowitz et al. (1993) found that either normal F9 or Hilo F9 prolonged the PT regardless of the tissue factor source, but the prolongation required high concentrations of factor IX when rabbit or human brain was used. With bovine thromboplastin, factor IX Hilo was significantly better than normal factor IX at prolonging the PT. In addition, the prolongation times depended on the amounts of factors IX and X used in the assays.
This variant has been designated factor IX Milano. See Bertina et al. (1989, 1990).
Sakai et al. (1989) found that the defect in hemophilia B (306900) (factor IX Kashihara), a severe hemorrhagic disorder in which a factor IX antigen is present in normal amounts but factor IX biological activity is markedly reduced, has a defect in valine-182 (equivalent to valine-17 in the chymotrypsin numbering system), which is replaced by phenylalanine. The change appears to hinder sterically the cleavage of arg180-val181 required for the activation of this zymogen.
This variant has been designated factor IX Cardiff II. See Taylor et al. (1989). One of the variant forms of hemophilia B in which normal levels of a dysfunctional factor IX protein is found is referred to as hemophilia B(M) (see 306900) (Hougie and Twomey, 1967; Kasper et al., 1977). The abnormal factor IX results in prolongation of the prothrombin time performed with ox brain thromboplastin. In 1 such patient, Taylor et al. (1990) found a G-to-C transversion at nucleotide 20524, changing the amino acid encoded at residue 182 from valine to leucine. The abnormal factor IX protein showed a normal molecular weight and normal calcium-binding properties. Activation of the mutant factor IX with factor XIa showed normal proteolytic cleavage. Hemophilia was clinically mild in these patients.
See Matsushita et al. (1989). The hemophilia (306900) was clinically severe.
Information was provided by Chen and Thompson (1989). The hemophilia (306900) was clinically severe.
See Green et al. (1989). The hemophilia (306900) was clinically severe.
In a severely affected, antigen-negative (CRM-negative) patient with hemophilia B (306900), Rees et al. (1985) found a point mutation in the F9 gene that changed an obligatory GT to a TT within the donor splice junction of exon 6. This was comparable to point mutations in splice junctions that lead to beta-zero-thalassemia (see 613985).
Information was provided by Chen and Thompson (1989). The hemophilia (306900) was clinically severe.
See Koeberl et al. (1989). The hemophilia (306900) was clinically moderate in severity.
A T-to-C substitution in codon 227 produced no change in amino acid (Koeberl et al., 1989).
See Koeberl et al. (1989). The hemophilia (306900) was clinically mild.
Matsushita et al. (1989) found a G-to-A substitution in the last nucleotide in the 3-prime acceptor splice site of IVS7. The hemophilia (306900) was severe and was associated with a serum inhibitor.
See Green et al. (1989).
This variant has been called factor IX Seattle-4 and factor IX Dreihacken.
See Chen et al. (1989). In a patient with hemophilia B (306900), Ludwig et al. (1992) identified a G-to-A transition at nucleotide 30864 of the F9 gene, resulting in replacement of arg248 by gln in the mature factor IX protein.
In male sibs with severe hemophilia B (306900), Chen et al. (1989) demonstrated a C-to-T change at nucleotide 30875 resulting in a nonsense mutation (TGA) and termination of protein synthesis at amino acid residue 252. The change involved a CpG dinucleotide. The protein was designated factor IX Portland.
See Koeberl et al. (1989). The hemophilia (306900) was clinically mild.
Information was provided by Chen and Thompson (1989). The hemophilia (306900) was clinically severe.
See Winship et al. (1989).
See Koeberl et al. (1989). Hemophilia B (306900) is an X-linked disorder relatively frequent among the Amish, particularly those living in Ohio (Wall et al., 1967). Ketterling et al. (1991) demonstrated that the Amish mutation is thr296-to-met. Among 64 families of European descent with hemophilia B, Ketterling et al. (1991) found that 6 (9%) had a C-to-T transition at base 31008 leading to the thr296-to-met mutation in the catalytic domain of factor IX. Five of the patients had the same haplotype and were known or presumed to be from the Amish group. All 6 patients had clinically mild disease.
See Bottema et al. (1989). The hemophilia (306900) was clinically mild.
See Thompson et al. (1989). The hemophilia (306900) was clinically severe.
See Wang et al. (1990). The hemophilia (306900) was clinically severe.
See Koeberl et al. (1989).
See Zhang et al. (1989). This mutation, due to a transition at a CpG dinucleotide, was found by Koeberl et al. (1990) in 2 patients with severe hemophilia B (306900).
Tsang et al. (1988) characterized the mutation in factor IX London-2, which caused a severe CRM+ hemophilia B (306900). Tsang et al. (1988) found a G-to-A transition at position 31119. The mutation resulted in substitution of glutamine for arginine at position 333. This arginine residue is conserved in the catalytic domain of normal human and bovine factor IX, factor X, and prothrombin. This mutation pinpoints a functionally critical feature of factor IX which may be involved in substrate or cofactor binding.
See Green et al. (1989). The hemophilia (306900) was clinically of moderate severity.
Ludwig et al. (1989) demonstrated a C-to-T transition at amino acid 338, converting the CGA codon for arginine to a TGA stop codon. The variant was called factor IX Bonn-1. The hemophilia (306900) was clinically severe.
Information was provided by Chen and Thompson (1989). The hemophilia (306900) was clinically of moderate severity.
Information was provided by Chen and Thompson (1989). The hemophilia (306900) was clinically of moderate severity.
See Spitzer et al. (1988). The hemophilia (306900) was clinically of moderate severity.
Information was provided by Chen and Thompson (1989). The hemophilia (306900) was clinically severe.
See Bertina et al. (1989, 1990).
Information was provided by Chen and Thompson (1989). The hemophilia (306900) was clinically severe.
Information was provided by Thompson (1989). The hemophilia (306900) was clinically of moderate severity.
Spitzer et al. (1988) found substitution of valine for alanine at position 390, resulting from a single base substitution (C-to-T) in exon 8. Sugimoto et al. (1988) demonstrated substitution of valine for alanine at position 390 in the catalytic domain as the molecular defect in factor IX Niigata. The patient had a moderately severe form of hemophilia B (306900) with a normal level of factor IX antigen but very low clotting activity.
Bertina et al. (1990) referred to this mutation as factor IX Lake Elsinore.
Attree et al. (1989) designed a strategy allowing rapid analysis of the critical serine protease catalytic domain of activated factor IX, encoded by exons 7 and 8 of the gene. The method involved enzymatic amplification of genomic DNA, analysis of the amplification products by denaturing gradient gel electrophoresis, and direct sequencing of the fragments displaying an altered melting behavior. They used this procedure to characterize 2 'new' mutations in hemophilia B (306900): factor IX Angers, a G-to-A substitution generating an arg in place of a gly at amino acid 396 of the mature factor IX protein; and factor IX Bordeaux, an A-to-T substitution introducing a nonsense codon in place of the normal codon for lys at position 411 (300746.0071). The hemophilia was clinically severe.
Ware et al. (1988) demonstrated that the defect in factor IX(Long Beach) is a result of a thymine-to-cytosine transition leading to the substitution of a threonine codon (ACA) for an isoleucine codon (ATA) in exon 8 of the F9 gene. In a case of hemophilia B (306900) of moderate severity, Geddes et al. (1989) found a mutation in the protease domain of factor IX that changed the codon for isoleucine-397 (ATA) to a threonine codon (ACA). The resulting abnormal protein had been named factor IX(Vancouver) (Geddes et al., 1987). Thus, factor IX Long Beach, factor IX Vancouver, and factor IX Los Angeles have the same defect. In 11 of 65 consecutive males with hemophilia B (17%), Bottema et al. (1990) found this mutation, a T-to-C transition at base 31311, which substitutes threonine for isoleucine-397. The 11 patients were of western European descent and had the same haplotype. Judging from the frequency of this haplotype, the probability of the same mutation occurring independently 11 times in this haplotype was considered to be minuscule. Despite the lack of overlapping pedigrees, a common ancestor for these patients was suspected. The clinical symptoms were considerably moderate/mild. Sarkar et al. (1991) found this mutation in 2 females with hemophilia B. Both were heterozygous, coming from unrelated families. Nonrandom X inactivation was proposed, although other possibilities included a second undetected intronic or promoter mutation. Chen et al. (1991) found this mutation in 7 families which all shared a rare haplotype, suggesting a common ancestor.
See Koeberl et al. (1989).
This variant has been designated factor IX Bordeaux. See Attree et al. (1989). The hemophilia (306900) was clinically severe.
Deletions of various sizes deleting exons 1-8 were reported by Giannelli et al. (1983), Anson et al. (1988), Taylor et al. (1988), Matthews et al. (1987), Ludwig et al. (1989), Wadelius et al. (1988), Bernardi et al. (1985), Mikami et al. (1987), Tanimoto et al. (1988), Koeberl et al. (1989), and Hassan et al. (1985). Some of the deletions were associated with development of inhibitors and others of comparable size were not. The hemophilia (306900) was clinically severe.
Ludwig et al. (1989) described deletion of exon 1 in a case of severe hemophilia B (306900).
See Ludwig et al. (1989). The hemophilia (306900) was severe and was associated with serum inhibitors.
Information was provided by Chen and Thompson (1989). The hemophilia (306900) was severe and was associated with serum inhibitors.
See Ludwig et al. (1989). The hemophilia (306900) was clinically severe.
See Vidaud et al. (1986). The hemophilia (306900) was clinically severe.
In a patient with moderate to severe hemophilia B (306900), Chen et al. (1988) found a large insertion in the F9 gene, which appeared to have originated from outside the gene rather than to represent an internal duplication. The variant was called factor IX El Salvador for the birthplace of the patient.
See Matthews et al. (1987) and Peake et al. (1989). The hemophilia (306900) was severe and was associated with serum inhibitors.
See Ludwig et al. (1989). The hemophilia (306900) was clinically severe.
This variant has been designated factor IX Seattle-2.
In a case of severe hemophilia B (306900), Schach et al. (1987) found deletion of a single adenine nucleotide in exon 5. This resulted in a frameshift that converted an aspartic acid at position 85 in the protein to a valine and the formation of a stop signal at position 86.
Winship (1990) found a substitution of valine by phenylalanine at residue 328 in exon h of factor IX in a patient with hemophilia B (306900) referred to as hemophilia B Oxford h5 (Oxh5). The substitution was caused by a G-to-T transversion at nucleotide 31103. Arg327-val328 is the major thrombin cleavage site in factor IX. Winship (1990) suggested that the mutant protein may have increased susceptibility to thrombin cleavage with resulting in vivo instability of the mutant protein.
In a 4-year-old boy with severe hemophilia B (306900), an isolated case in his family, Montandon et al. (1990) identified a C-to-T transition at residue 17762 resulting in a translation stop at codon arginine-116. A second mutation in this patient at residue 30890 resulted in a his257-to-tyr substitution (300746.0085); this mutation was subsequently shown to be neutral by the fact that its origin preceded the maternal grandfather and it produced no reduction in factor IX coagulant and antigen level in the grandfather. On the other hand, analysis of other family members showed that the mutation for arg116-to-ter had occurred at gametogenesis in the paternal grandfather. The patient was referred to as Malmo 7.
See 300746.0084.
Taylor et al. (1991) described a male patient with hemophilia B (306900) in whom they documented somatic mosaicism for a cysteine-to-serine alteration at codon 350 in the catalytic domain of factor IX. The mutation resulted from a G-to-C transversion at nucleotide 31170. Using a combination of allele-specific oligonucleotide hybridization and differential termination of primer extension, Taylor et al. (1991) showed that hepatic, renal, smooth muscle, and hematopoietic cells possessed both normal and mutant factor IX sequences. An additional unusual phenomenon in this pedigree was the presence of 2 females in successive generations with moderately severe factor IX deficiency. These females were the daughter and granddaughter of the proband. No evidence of X chromosome or autosome cytogenetic abnormalities was found, no additional sequence alterations were identified in the factor IX gene in either woman and no gross changes were observed on Southern analysis of the regulatory regions in the 5-prime and 3-prime ends of the gene. The normal X chromosomes of the 2 women were shown to have different haplotypes at the factor IX locus. Taylor et al. (1991) speculated that the X chromosome bearing the normal factor IX gene has been exclusively inactivated in both affected women, possibly secondary to a second genetic change affecting the primary inactivation center on the mutant X chromosome and resulting in a failure of inactivation of the mutant factor IX sequences.
Winship and Dragon (1991) described a G-to-A transition at nucleotide 10442 of the F9 gene, resulting in substitution of asparagine for aspartic acid-64 (D64N). The change resulted in a functionally defective factor IX molecule that altered calcium-binding properties.
In an Anglo-Irish family living in New Zealand, Royle et al. (1991) identified a T-to-C transition at position +8 in the promoter region of the F9 gene as the cause of hemophilia B Leyden (see 306900). This mutation is situated within the repeat consensus sequence in the transcribed but untranslated portion of the gene. The mutation had arisen de novo in the proband.
In a 3-year-old boy with hemophilia B Leyden (306900), Picketts et al. (1992) described an A-to-T transversion at position -5 of the factor IX promoter. Picketts et al. (1993) identified 5 transcription factor binding sites within the F9 promoter and showed that the Leyden mutation at nucleotide -5 interfered with the binding of proteins to 1 of 3 newly identified sites. The correlation between the postpubertal recovery of these mutants and the induction of the transcription factor DBP (D-site binding protein; 124097) led Picketts et al. (1993) to the discovery of a synergistic interaction between DBP and C/EBP (CCAAT/enhancer binding protein; 116897).
As indicated in 300746.0004, Reitsma et al. (1989) found an A-to-G mutation at position +13 of the factor IX gene in an American patient of Armenian descent with hemophilia B Leyden (see 306900).
In a patient with hemophilia B (306900), Miyata et al. (1991) identified a G-to-A substitution in exon 8 resulting in replacement of glycine-311, a highly conserved amino acid residue among serine proteases, by glutamic acid. The mutation resulted in complete loss of both coagulant activity and esterase activity. The variant was designated factor IX Amagasaki.
In a 17-year-old male with severe hemophilia B (306900), Solera et al. (1992) found a 4,442-bp deletion, which removed both the donor splice site located at the 5-prime end of intron d and the last 2 coding nucleotides located at the 3-prime end of exon 4. This fragment had been replaced by a 47-bp sequence from the normal factor IX gene, inserted in inverted orientation. They identified 2 homologous sequences at the ends of the deleted DNA fragment. The variant was designated factor IX Madrid-2.
Ludwig et al. (1992) described the molecular basis of hemophilia B (306900) in 5 patients who had neither deletions nor rearrangements of the F9 gene. By enzymatic amplification and sequencing of all exons and promoter regions, a causative mutation in the protease domain was identified in each patient. The first was a G-to-T transversion at nucleotide 31215, leading to substitution of isoleucine for serine-365. The variant was designated factor IX Schmallenberg.
In a patient with hemophilia B (306900), Ludwig et al. (1992) demonstrated an A-to-G transition at nucleotide 31214 resulting in replacement of serine-365 by glycine. The variant was designated factor IX Varel. The mutation occurs at the same codon as that involved in factor IX Schmallenberg (300746.0093). This patient also had a silent mutation (GAT to GAC) at asp364. Thus, this patient had a double basepair substitution of TA to CG at nucleotides 31213 and 31214 but only a single amino acid change of ser365-to-gly. This patient also developed an antibody to factor IX during replacement therapy, which suggested that deletion of the factor IX gene is not necessary for development of antibody.
In a patient with hemophilia B (306900), Ludwig et al. (1992) identified a G-to-C transversion at nucleotide 31211, resulting in substitution of his for asp364. The variant was designated factor IX Mechtal.
In a patient with hemophilia B (306900), Ludwig et al. (1992) identified an A-to-T transversion at nucleotide 30855, resulting in substitution of valine for glutamic acid-245. The variant was designated factor IX Monschau.
Unlike other F9 promoter mutations which result in hemophilia B Leyden (see 306900) (e.g., 300746.0001), this promoter mutation, a G-to-C change at -26, is accompanied by a bleeding tendency that is not ameliorated after puberty (Reijnen et al., 1992). Reijnen et al. (1992) demonstrated that this mutation disrupted the binding of hepatocyte nuclear factor-4 (HNF4; 600281), a member of the steroid hormone receptor superfamily of transcription factors, which normally binds at nucleotides -34 to -10. Whereas HNF4 transactivated the wildtype promoter sequence in liver and nonliver (e.g., HeLa) cell types, it did not at all transactivate the -26 mutated promoter.
Crossley et al. (1992) provided an explanation for why the -20 promoter mutation shows recovery at puberty and the -26 Brandenburg mutation does not. Both mutations impair transcription by disrupting the binding site for the liver-enriched transcription factor LF-A1/HNF4. The -26 but not the -20 mutation also disrupts an androgen-responsive element, which overlaps the LF-A1/HNF4 site. This explains the failure of improvement in -26 patients.
In a patient with severe hemophilia B (306900), Vidaud et al. (1993) discovered a de novo insertion of a human-specific Alu repeat element within exon 5 of the F9 gene. The element interrupted the reading frame of the mature factor IX at glutamic acid 96 resulting in a stop codon within the inserted sequence. The Alu repeat was 322 bp long and was thought to have been inserted through retroposition. Insertional mutagenesis involving an Alu element has been reported in type I neurofibromatosis (162200.0001) and in gyrate atrophy (258870.0023). The involvement of Alu elements in gene deletion through homologous recombination and unequal crossing-over has been demonstrated in familial hypercholesterolemia (e.g., 143890.0029) and ADA deficiency (102700.0008). Also see Vidaud et al. (1989).
Note: This allelic variant was previously incorrectly in OMIM as EX51INS in 300746.0080.
Among the many mutations of the F9 gene described in hemophilia B (306900) (Giannelli et al., 1992), the density of amino acid substitutions in the domains coded by the different exons is similar, except for exon 'a' where it is much lower. Exon 'a' codes for the predomain of the signal peptide that is necessary for the transport of factor IX to the endoplasmic reticulum and for its secretion. Comparison of the signal peptide of secreted proteins shows lack of conservation of the primary amino acid sequence, and the only constant features are the presence of a charged residue at the amino end and a core of 8-12 hydrophobic residues. In a patient with severe, antigen-negative hemophilia B, Green et al. (1993) found an A-to-T transversion causing substitution of isoleucine by asparagine at position -30. This change disrupted the hydrophobic core of the prepeptide, a feature required for secretion. Thus, hemophilia in this patient was caused by failure to secrete factor IX from the hepatocytes. Only one other amino acid substitution had been reported in the prepeptide of factor IX; a cys-to-arg mutation at position -19 affecting the cleavage site between the pre- and propeptide (cys-19/thr-18) caused mild hemophilia (Bottema et al., 1991) (300746.0100).
See 300746.0099.
Aguilar-Martinez et al. (1994) identified a val373-to-glu mutation in a 40-year-old man in whom the diagnosis of hemophilia (306900) was made at the age of 4 and who had been suffering hemarthrosis since the age of 13. A first cousin was affected. The mutation was located in the serine protease catalytic domain of the F9 gene.
Pezeshkpoor et al. (2018) noted that ala-10thr (A-10T) is the legacy designation for ala37-to-thr (A37T). The A37T designation includes the F9 signal sequence.
The propeptide sequences of the vitamin K-dependent clotting factors serve as a recognition site for the enzyme gamma-glutamyl carboxylase (137167), which catalyzes the carboxylation of glutamic acid residues in the amino terminus of the mature protein. Chu et al. (1996) described a mutation in the propeptide of factor IX that resulted in warfarin sensitivity (301052) because of reduced affinity of the carboxylase for the factor IX precursor. The patient was a 49-year-old with a congenital bicuspid aortic valve with accompanying aortic stenosis and regurgitation. After insertion of an artificial valve, he had bleeding complications when he was given warfarin for anticoagulation. The patient's family history was negative for bleeding diatheses. The patient had a factor IX activity level of more than 100% when not receiving warfarin and less than 1% when receiving warfarin, at a point where other vitamin K-dependent factors were at 30 to 40% activity levels. Direct sequence analysis of amplified genomic DNA from all 8 exons and exon-intron junctions showed a G-to-A transition at nucleotide 6346 resulting in an alanine-to-threonine change at residue -10 in the propeptide. To define the mechanism by which the mutation resulted in warfarin sensitivity, they analyzed wildtype and mutant recombinant peptides in an in vitro carboxylation reaction. The peptides that were analyzed included the wildtype sequence of F9, the ala-10thr sequence, and the ala-10gly substitution which reflects the sequence in bone gamma-carboxyglutamic acid protein (112260). Measurement of carbon dioxide incorporation at a range of peptide concentrations demonstrated about twice normal V(max) values for both A-10T and A-10G, whereas K(m) values showed a 33-fold difference between wildtype and the variants. These studies delineated a novel mechanism for warfarin sensitivity and explained the observation that bone gamma-carboxyglutamic acid protein is more sensitive to warfarin than the coagulation proteins.
Pezeshkpoor et al. (2018) reported that 11 patients with X-linked warfarin sensitivity, including 6 patients previously by Oldenburg et al. (2001), were found to have an A37T mutation in exon 2 of the F9 gene. The mutation, which occurs in a highly conserved region of the protein, was not identified in 1,834 female and 135 male healthy blood donors from different regions throughout Europe. Expression of F9 containing the A37T mutation in HEK293T cells resulted in a reduction in the FIX:C ratio and a reduced half maximal inhibitory concentration (IC50) for warfarin compared to HEK293T cells transfected with wildtype F9. This indicated a sensitivity to warfarin conferred by the A37T mutation.
Pezeshkpoor et al. (2018) noted that ala-10val (A10V) is the legacy designation for ala37-to-val (A37V). The A37V designation includes the signal sequence.
Oldenburg et al. (1997) reported 3 patients in whom mutations in the factor IX propeptide was found to cause severe bleeding during coumarin therapy (301052). Strikingly, the bleeding occurred within the therapeutic ranges of the prothrombin time (PT) and international normalized ratio (INR). In all 3 patients, coumarin therapy caused an unusually selective decrease of factor IX activity to levels below 1 to 3%. Upon withdrawal of coumarin, factor IX levels increased to subnormal or normal values of 55, 85 and 125%, respectively. In 1 patient the ala-10-to-thr mutation (300746.0102) was found; in 2 patients the missense mutation affecting the ala-10 residue was ala (GCC) to val (GTC). The mutation in the propeptide at a position that is essential for the carboxylase recognition site causes a reduced affinity of the carboxylase enzyme to the propeptide. This effect leads to an impaired carboxylase epoxidase reaction that is decisively triggered by the vitamin K concentration.
Pezeshkpoor et al. (2018) reported that 7 patients with X-linked warfarin sensitivity, including 5 patients previously reported by Oldenburg et al. (2001), were found to have an A37V mutation in exon 2 of the F9 gene. The mutation, which occurs in a highly conserved region of the protein, was not identified in 1,834 female and 135 male healthy blood donors from different regions throughout Europe. Expression of F9 containing the A37V mutation in HEK293T cells resulted in a reduction in the FIX:C ratio and a reduced half maximal inhibitory concentration (IC50) for warfarin compared to HEK293T cells transfected with wildtype F9. This indicated a sensitivity to warfarin conferred by the A37V mutation.
Chan et al. (1998) found that a 20-year-old female student with mild hemophilia B (306900) was heterozygous for a mutation in codon 351 of the F9 gene: GCT (ala) was converted to CCT (pro). She had inherited the mutation from her carrier mother. Analysis of the methyl-sensitive HpaII sites at the 5-prime end of the hypoxanthine phosphoribosyltransferase gene (HPRT; 308000) showed that skewed inactivation of the X chromosome carrying her normal F9 gene accounted for the hemophilia phenotype.
Drost et al. (2000) demonstrated that nucleotide 17747 of the F9 gene is a mutation hotspot for hemophilia B (306900) in all Latin American population samples but not in other populations. Two substitutions were observed, G-A and G-C (300746.0106). The authors suggested that this was the first evidence of population-specific effects on germline mutation that causes human genetic disease.
See (300746.0105) and Drost et al. (2000).
In a woman with moderately severe hemophilia B (306900), Costa et al. (2000) found a T-to-C transition at position +2 in the 5-prime splice site of intron 3 (6704T-C) and an ile344-to-thr missense mutation (306900.0108). The splice site mutation came from the mother who was a somatic mosaic; the missense mutation appeared to be a de novo mutation from the father.
See 300746.0107 and Costa et al. (2000).
Taylor et al. (1992) found that the causative mutation in the first reported patient with Christmas disease (306900) (Biggs et al., 1952) was a cys206-to-ser change in the F9 gene. The patient died at the age of 46 years from acquired immunodeficiency syndrome, contracted through treatment with blood products (Giangrande, 2003).
Cutler et al. (2004) described a family in which the maternal grandfather of a severely affected infant with hemophilia B (306900) was a somatic and germline mosaic and had very mild factor IX deficiency. The maternal grandfather was apparently a somatic and germline mosaic for the family mutation, a 2-bp deletion (AG within codons 134-135) in the F9 gene causing a frameshift mutation and the creation of a premature termination sequence in exon 6 at codon 141. One daughter, the mother of the proband, was a carrier of the mutation; the other daughter, was not a carrier.
In a patient with a mild form of hemophilia B (306900), Ketterling et al. (1994) identified a G-to-C transversion in the F9 gene, resulting in an arg338-to-pro (R338P) substitution. There was 16% residual F9 activity.
This mutation is known as factor IX Padua.
In a 21-year-old Italian man with thrombophilia and a deep venous thrombosis in the right leg (300807), Simioni et al. (2009) identified a hemizygous 31134G-T transversion in exon 8 of the F9 gene, resulting in an arg338-to-leu (R338L) substitution. Coagulation studies showed that he had normal levels of F9 antigen, but very high levels of F9 activity (776% of control values). His 11-year-old brother and mother, who were hemizygous and heterozygous for the mutation, respectively, also had normal F9 antigen levels and increased F9 activity levels (551% and 337%, respectively). The mutation was not found in 200 control individuals or in 200 patients with documented thromboembolism. In vitro functional expression studies showed that the mutant F9 had 8-fold increased activity compared to wildtype, consistent with a gain of function. The affected residue is important for binding to F10 (see 227600), and the R338L substitution apparently increases the efficiency of this binding. Simioni et al. (2009) noted that another mutation at this residue, R338P (300746.0111), results in hemophilia B (306900).
Although the X-linked blood disorder known as the 'royal disease' transmitted from Queen Victoria (1819-1901) to European royal families had been known to be a form of hemophilia, its molecular basis had not been established. In the remains of the Russian Empress Alexandra, granddaughter of Queen Victoria, and her son, Crown Prince Alexei, Rogaev et al. (2009) identified an A-to-G transition at the -3 position of intron 3 of the F9 gene. The mutation activated a cryptic splice acceptor site, shifting the open reading frame of the F9 mRNA and leading to a premature stop codon. The mutation was also identified in one of Alexei's sisters, presumed to be Anastasia. The identification of this mutation in the F9 gene allowed the recognition of the 'royal disease' as a severe form of hemophilia B, also known as 'Christmas disease' (306900).
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