Alternative titles; symbols
Other entities represented in this entry:
SNOMEDCT: 41788008, 767712006; ICD10CM: D67; ICD9CM: 286.1; ORPHA: 169793, 169796, 169799, 177929, 98879; DO: 12259;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xq27.1 | Hemophilia B | 306900 | X-linked recessive | 3 | F9 | 300746 |
A number sign (#) is used with this entry because hemophilia B (HEMB), also known as Christmas disease, is caused by mutation in the gene encoding coagulation factor IX (F9; 300746).
Hemophilia B (HEMB), which results from factor IX deficiency, is phenotypically indistinguishable from hemophilia A (306700), which results from coagulation factor VIII (F8; 300841) deficiency. The classic laboratory findings in hemophilia B include a prolonged activated partial thromboplastin time (aPTT) and a normal prothrombin time (PT) (Lefkowitz et al., 1993).
Early studies made a distinction between cross-reactive-material (CRM)-negative and CRM-positive hemophilia B mutants. This classification referred to detection of the F9 antigen in plasma, even in the presence of decreased F9 activity. Detection of the antigen indicated the presence of a dysfunctional F9 protein. Roberts et al. (1968) found that about 90% of patients with hemophilia B were CRM-negative, whereas about 10% were CRM-positive. However, Bertina and Veltkamp (1978) found that a rather large proportion of the hemophilia B patients could be characterized as hemophilia B CRM+. They identified 14 cases of hemophilia B CRM+ from 11 families among a group of 33 patients. After immunologic and activity comparisons, they found at least 7 different factor IX variants. Bertina and Veltkamp (1978) noted the high heterogeneity within this group. 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. At least one variant of factor VII (Padua) was also known.
Aggeler et al. (1952) described a 16-year-old white male with a hemophilia-like disorder in which there appeared to be a deficiency of a coagulation factor, which the authors called 'plasma thromboplastin component' (PTC). They cited reports indicating that blood from some patients with hemophilia was capable of correcting the coagulation defect in other cases of hemophilia in vitro. The authors concluded that these patients had a combined defect of PTC deficiency and 'true' hemophilia (hemophilia A). It was not clear at that time if the disorder was hereditary.
Biggs et al. (1952) in the December 27 (Christmas) issue of the British Medical Journal reported a 5-year-old boy, with a surname of 'Christmas' who had this disorder, as well as other patients, some of whom came from families showing a typical X-linked pattern of inheritance, Biggs et al. (1952) defended the familial eponym in the following way: 'The naming of clinical disorders after patients was introduced by Sir Jonathan Hutchinson and is now familiar from serological research; it has the advantage that no hypothetical implication is attached to such a name.' Giangrande (2003) provided historical information concerning the patient Stephen Christmas (1947-1993), whose mutation in the F9 gene (300746.0109) was reported by Taylor et al. (1992) and his physicians.
Hemophilia B(M)
A subset of hemophilia B patients have a prolonged prothrombin time when exposed to bovine (or ox) brain tissue, which serves as a source of thromboplastin, or tissue factor (F3; 134390); these CRM+ patients are classified as having hemophilia B(M) (Lefkowitz et al., 1993).
Several workers (e.g., Nour-Eldin and Wilkinson, 1959) observed the combination of factor IX deficiency with factor VII (F7; 613878) deficiency. However, inheritance was always X-linked, even though F7 is on chromosome 13. Verstraete et al. (1962) reported 4 families in which all affected males had both Christmas disease and factor VII deficiency. The authors suggested that factor VII deficiency was a consistent secondary phenomenon; thus no separate mutation for the combined defect would be necessary.
Hougie and Twomey (1967) defined a variant of hemophilia B that differed from the usual form by the presence of a prolonged PT. They presented evidence these patients had a structurally abnormal and inactive form of factor IX that acted as an inhibitor of the normal reaction between factor VII and bovine brain. They called the variant hemophilia B(M), after the initial of the family surname.
Denson et al. (1968) identified 3 blood samples of hemophilia B(M) among samples derived from 27 patients with Christmas disease. In a series of coagulation assays, Denson et al. (1968) demonstrated that the prolongation of the PT involved inhibition of the reaction between ox brain tissue factor, factor VII, and factor X. Noting that this distinct abnormality had only been observed in patients with factor IX deficiency, the authors postulated that the 'inhibitor' may be an abnormal protein similar to or identical with factor IX. Subsequent studies showed that this inhibitor was an abnormal form of factor IX that was functionally inactive but was antigenically indistinguishable from normal factor IX.
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 (300746.0031), 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.
Hemophilia B Leyden
Veltkamp et al. (1970) described a variant of hemophilia B, termed hemophilia B Leyden, 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 mutation in the promoter region of the F9 gene (300746.0001). The findings suggested that a point mutation could lead to a switch from constitutive to steroid hormone-dependent gene expression. The families were probably related.
Mandalaki et al. (1986) reported a 5-generation Greek family with hemophilia B. The factor IX levels in the 3 patients from the last generation were extremely low, while those of patients in the older generations were much higher. In 1 patient, the rise of factor IX levels appeared between ages 13 and 14 years. In addition, older patients in the family had much milder symptoms compared to the younger patients. The phenotype was similar to hemophilia B Leyden as described by Veltkamp et al. (1970).
Manifesting Females
Lascari et al. (1969) described a daughter of a male with hemophilia B who had an XX karyotype, factor IX level of 5%, and hemarthrosis. The factor IX level in the mother was 100%. The girl was thought to be a manifesting heterozygote with unfortunate lyonization.
Spinelli et al. (1976) observed deletion of the short arm of 1 of the X chromosomes in a female with hemophilia B. Family investigations were negative. Hashmi et al. (1978) reported a girl with Christmas disease. Her father was affected, and her parents were related as first cousins, suggesting possible homozygosity for the defect. They referred to a similar instance of plausible homozygosity.
Wadelius et al. (1993) reported a female with hemophilia B with factor IX activity of about 1%. Her father had severe hemophilia B. No chromosomal abnormality could be detected, and DNA analysis gave no indication of deletions or mutations of TaqI cleavage sites in the F9 gene. Analysis of the methylation pattern of locus DXS255 indicated that the expression of hemophilia B in this girl was caused by nonrandom X inactivation.
Vianna-Morgante et al. (1986) observed de novo t(X;1)(q27;q23) in a girl with hemophilia B who had no affected relatives. In a full description of the case, Krepischi-Santos et al. (2001) stated that the translocated X was preferentially active and that methylation analysis of the DXS255 locus confirmed the skewed X inactivation with the paternal allele being the active one. Molecular analysis showed deletion of at least part of the F9 gene.
Nisen et al. (1986) described hemophilia B in a girl with the karyotype 46,X,del(X)q27. They showed that the X chromosome with the deletion was inactivated in all cells. The mother's identical twin sister had a son with severe hemophilia B. The proband was also lacking the paternal factor VIII gene, indicating that the deletion had occurred in the paternal X chromosome and had included the factor VIII locus. However, both the maternal and the paternal factor IX loci were present. The interpretation applied by Nisen et al. (1986) was that inactivation of the deleted, paternally derived X chromosome in all cells had provided the opportunity for expression of the hemophilia B gene which the proband had inherited from her mother.
By sequencing the complete factor IX gene in 2 sisters with hemophilia B with different phenotypes and no family history of hemorrhagic diathesis, Costa et al. (2000) found a common 5-prime splice site mutation in intron 3 (300746.0107) and an additional missense mutation (I344T; 300746.0108) in 1 sister. The presence of dysfunctional antigen in the latter strongly suggested that these mutations were in trans. Neither mutation was found in leukocyte DNA from the asymptomatic parents, but the mother was a somatic mosaic for the shared splice site mutation. The somatic mosaicism in the mother for the splice site mutation was demonstrated by studies of buccal and uroepithelial cells. The missense mutation was presumed to have resulted from a de novo mutation in the father's gametes. The compound heterozygous proband was a 14-year-old girl with moderate hemophilia B, manifest by hematomas, hemarthrosis, and epistaxis. A sister suffered only from rare hematomas.
In a population-based survey in the Netherlands, Plug et al. (2006) found that female carriers of hemophilia A and B bled more frequently than noncarrier women, especially after medical procedures, such as tooth extraction or tonsillectomy. Reduced clotting factor levels correlated with a mild hemophilia phenotype. Variation in clotting levels was attributed to lyonization.
Chronic synovitis occurs in about 10% of Indian patients with severe hemophilia. Ghosh et al. (2003) reported an association between the development of chronic synovitis in patients with hemophilia and the HLA-B27 allele (142830.0001). They studied 473 patients, 424 with hemophilia A and 49 with hemophilia B. Twenty-one (64%) of 33 patients with both disorders had HLA-B27, compared to 23 (5%) of 440 with severe hemophilia without synovitis (odds ratio of 31.6). There were 3 sib pairs with hemophilia in whom only 1 sib had synovitis; all the affected sibs had the HLA-B27 allele, whereas the unaffected sibs did not. Chronic synovitis presented as swelling of the joint with heat and redness and absence of response to treatment with factor concentrate. Ghosh et al. (2003) suggested that patients with HLA-B27 may not be able to easily downregulate inflammatory mediators after bleeding in the joints, leading to chronic synovitis.
Hemophilia B is classically transmitted as an X-linked recessive disorder. Cutler et al. (2004) described a family in which the usual pattern of X-linked inheritance of hemophilia B was complicated by mosaicism in the proband's maternal grandfather. The proband was a male infant with severe factor IX deficiency who was initially thought to be a sporadic case. Testing of other family members identified his mother as a carrier and his asymptomatic maternal grandfather as having very mild factor IX deficiency. The causative mutation was identified as a 2-bp deletion (AG within codons 134-135) in the F9 gene (300746.0110).
Acquired Inhibitor
The treatment for factor IX deficiency is replacement of the missing coagulation factor by transfusion of plasma from a healthy individual. However, a subset of patients develop IgG antibodies against normal factor IX, which complicates treatment. George et al. (1971) reported a family in which 3 of 4 members with Christmas disease developed an inhibitor to factor IX after transfusion. The inhibitor was an IgG antibody directed against the activated form of factor IX (IXa). There was no immunologically detectable factor IX-like material in the affected family members without an inhibitor. The findings were consistent with previous postulates that inhibitors to factor IX develop only in patients with Christmas disease who lack the factor IX antigen. The fourth member of the family, who had no factor IX antigen, was transfused several times, but failed to develop antibodies to factor IX. George et al. (1971) noted that inhibitors to factor IX develop infrequently compared to factor VIII, suggesting that there may be a predisposition to the development of an inhibitor.
Giannelli et al. (1983) noted that treatment of patients with factor IX deficiency with normal plasma resulted in the development of specific anti-F9 antibodies in about 1% of all cases and about 2.5% of severe cases. The authors postulated that this may be due to complete absence of 'self' factor IX in the plasma recipient, such that the immune system regards the infused normal factor IX as foreign. Indeed, 4 patients with factor IX deficiency and F9 antibodies were found to have gross deletions in the F9 gene, resulting in complete absence of the protein.
In a patient with severe F9 deficiency who had developed a high-titer antibody, Hassan et al. (1985) observed a deletion of about 33 kb at the F9 locus.
By Southern blot analysis of 9 patients, including 2 brothers, with hemophilia B and F9 antibodies, Matthews et al. (1987) found that 2 had a total deletion of the F9 gene. The brothers were shown to have a presumably identical complex rearrangement of the gene involving 2 separate deletions. Five other patients had a structurally intact F9 gene. Matthews et al. (1987) concluded that whereas large structural defects in the F9 gene can predispose the patients to the development of antibody, the phenomenon can also be associated with other defects of the gene.
Green et al. (1988) identified a partial deletion in the F9 gene in a boy and his uncle, both of whom had hemophilia B and inhibitors to factor IX. The mother of the boy was a carrier. The deletion, called 'London-1,' most likely arose by nonhomologous recombination.
Wadelius et al. (1988) found total deletion of the F9 gene in 3 affected males in 1 family who did not have antibodies against native factor IX. Two of the patients, who were cousins, had inherited the same maternal HLA haplotype, suggesting that immune gene(s) located at the MHC locus may be important for the development of antibodies against factor IX.
Ljung et al. (2001) found that 11 (23%) of 48 patients with severe hemophilia B developed inhibitors and all of them had deletions or nonsense mutations. Thus, 11 of 37 (30%) patients with severe hemophilia B as a result of deletion/nonsense mutations developed inhibitors compared with none of 11 patients with missense mutations.
In a patient with severe F9 deficiency who developed an inhibitor, Peake et al. (1984) detected a deletion in the F9 gene using 4 genomic gene probes. Similar studies of 8 female relatives using this method identified 2 as carriers. Used a genomic probe containing a TaqI polymorphism in the F9 gene, Giannelli et al. (1984) successfully identified carriers of Christmas disease in 3 affected families.
In eukaryotic DNA, a high proportion of CpG dinucleotides are methylated at the cytosine residue to give 5-methylcytosine. The restriction enzyme HhaI will not cleave at methylated CpG sites, but PCR can overcome this limitation. Winship et al. (1989) used PCR to detect a polymorphic HhaI site located 8 kb 3-prime to the F9 gene and estimated that almost half of female subjects can be expected to be heterozygous at this site. Detection of this marker using PCR was predicted to increase the proportion of persons in whom the carrier state of hemophilia B could be diagnosed, compared to using the restriction enzyme alone, which could be influenced by methylation status.
Koeberl et al. (1990) compared RFLP-based carrier detection of an X-linked disease with a direct method involving genomic amplification with transcript sequencing (GAWTS). They pointed out that the RFLP approach 'suffers from multiple levels of uncertainty.' They found that 22 at-risk females were diagnosed by direct testing, whereas only 11 females could be diagnosed by standard RFLP analysis.
Giannelli et al. (1992) used hemophilia B as a model of a genetic disease with marked mutational heterogeneity to lay out an overall strategy for genetic counseling. They started with the construction of a national database which could be used for diagnosis and genetic counseling on the basis of DNA abnormality. In the U.K. there were just over 1,000 patients with hemophilia B and these were probably derived from 500 to 600 families. They characterized the mutation in a group of unrelated patients and in only 1 of 170 patients examined from the Swedish and British series did they fail to find a mutation in the essential regions of the gene. Thus the screening procedures used were capable of detecting all types of mutations. By phenotype/genotype correlations the authors generated information of prognostic value concerning each of those mutations.
Prenatal Diagnosis
In 5 kindreds studied in detail, Poon et al. (1987) were able to determine the carrier status of hemophilia B in all 11 females at risk; prenatal diagnosis could be offered to the offspring of each of the 6 carriers identified.
Green et al. (1991) suggested a strategy for facilitating carrier and prenatal diagnosis by identification of all hemophilia B mutations in a given population so that only the relevant parts of the molecule need be focused on when performing amplification mismatch detection (AMD) as developed by Montandon et al. (1989).
Linkage studies in the early 1960s suggested that the hemophilia A and B loci were not allelic; hemophilia A was found to be tightly linked to colorblindness (CBD; 303800) on Xq28, whereas hemophilia B apparently was not linked to colorblindness. In the dog, Brinkhous et al. (1973) showed that the loci for hemophilias A and B were probably 50 map units or more apart. The genetic distance between the 2 loci was estimated to be about 50 map units in man as well.
By in situ hybridization, Purrello et al. (1985) showed that the loci for hemophilia A and hemophilia B flank the fragile X site (300624). The authors believed that this finding, combined with the knowledge that hemophilia B recombines freely with at least 2 loci of the G6PD (305900) cluster, supported the Siniscalco hypothesis that the chromosomal segment in which the fragile X site occurs is normally a region of high meiotic recombination (Szabo et al., 1984).
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.
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 Taq1 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.
Rogaev et al. (2009) identified a splice site mutation in the F9 gene (300746.0113) as the causative mutation for the 'Royal disease,' the form of hemophilia transmitted from Queen Victoria to European royal families and transmitted to her granddaughter, Russian Empress Alexandra and her son, Crown Prince Alexei.
Mutation Rate
In an analysis of 1,485 families with hemophilia A or hemophilia B, Barrai et al. (1985) estimated the proportion of sporadic cases to be 0.166 and 0.078, respectively. The age of maternal grandfathers at birth of the mother of hemophilia B cases was higher than that of appropriate controls.
In the population of families with hemophilia B at the Malmo Haemophilia Centre, Montandon et al. (1992) estimated that the overall mutation rate was 4.1 x 10(-6) and that the ratio of male to female specific mutation rates was 11. Three of 13 isolated cases had a new mutation, whereas the other 10 had mothers who carried a new mutation.
Kling et al. (1992) found that 24 of 45 hemophilia B patients in Malmo, Sweden, had no affected family members. Three of 13 families with 1 patient available for study had a do novo mutation, whereas the defect was inherited from a carrier mother in the remaining 10. All 10 of these carrier mothers had de novo mutation, as their fathers were phenotypically normal and the grandmothers were noncarriers. In all 6 of the 10 cases in whom RFLP patterns were informative, the mutation was of paternal origin, and the average age of the father at the birth of the new carrier female was 41.5 years. These data supported a paternal age effect and a higher mutation rate in males than in females regarding factor IX mutations.
Among 43 families with hemophilia B, Ketterling et al. (1993) found that 25 had a mutation in the female germline and 18 in the male germline. The excess of germline origins in females did not imply an overall excess mutation rate per basepair, because when the mother and maternal grandparents were analyzed, the excess of X chromosomes in females, 4:1, skewed the data in favor of female origins. Bayesian analysis corrected for this bias and indicated that the 25:18 ratio actually represented a predominance of mutations in males. Transitions at the dinucleotide CpG, estimated to account for 36% of mutations in the F9 gene (Koeberl et al., 1990), showed the most striking male predominance of mutation, 11:1. This finding was comparable with previous data suggesting that methylation at CpG dinucleotides is reduced or absent in the female germline (Driscoll and Migeon, 1990). This effect, rather than an increased number of replications in the male germ cells, likely accounted for the male excess.
In studies of the patterns of independent mutation resulting in hemophilia B in 127 Caucasian and 44 non-Caucasian patients, Gostout et al. (1993) could find no differences, suggesting either predominance of endogenous processes or common mutagen exposure rather than mutagen exposure specifically associated with non-Caucasian status or non-Western life style.
Green et al. (1999) conducted a population-based study of hemophilia B mutations in the United Kingdom in order to construct a national confidential database of mutations and pedigrees to be used for the provision of carrier and prenatal diagnoses based on mutation detection. This allowed the direct estimate of overall mutation rate, male mutation rate, and female mutation rate for hemophilia B. The values obtained per gamete per generation and the 95% confidence intervals were 7.73 (6.29-9.12) x 10(-6) for overall mutation rate; 18.8 (14.5-22.9) x 10(-6) for male mutation rate; and 2.18 (1.44-3.16) x 10(-6) for female mutation rate. The ratio of male-to-female mutation rates was 8.64 (95% CI, 5.46-14.5). Attempts to detect evidence of gonadal mosaicism for hemophilia B mutation in suitable families did not detect any instances of ovarian mosaicism in 47 available opportunities. This suggested that the risk of a noncarrier mother manifesting as a gonadal mosaic by transmitting the mutation to a second child should be less than 0.062.
Giannelli et al. (1999) also estimated the rates per base per generation of specific types of mutations, using their direct estimate of the overall mutation rate for hemophilia B and information on the mutations present in the U.K. population as well as those reported year by year in the hemophilia B world database. These rates were as follows: transitions at CpG sites, 9.7 x 10(-8); other transitions, 7.3 x 10(-9); transversions at CpG sites, 5.4 x 10(-9); other transversions, 6.9 x 10(-9); and small deletions/insertions causing frameshifts, 3.2 x 10(-10).
Ketterling et al. (1999) estimated the male:female ratio of mutations in the F9 gene by Bayesian analysis of 59 families. The overall ratio was estimated at 3.75. It varied with the type of mutation, from 6.65 and 6.10 for transitions at CpG and A:T to G:C transitions at non-CpG dinucleotides, respectively, to 0.57 and 0.42 for microdeletions/microinsertions and large deletions (more than 1 kb), respectively. The value for the 2 subsets of non-CpG transitions differed (6.10 for A:T to G:C vs 0.80 for G:C to A:T). Somatic mosaicism was detected in 11% of the 45 'origin individuals' for whom the causative mutation was visualized directly by genomic sequencing of leukocyte DNA (estimated sensitivity of approximately 1 part in 20). Four of the 5 defined somatic mosaics had G:C to A:T transitions at non-CpG dinucleotides, hinting that this mutation subtype may occur commonly early in embryogenesis. The age at conception was analyzed for 41 U.S. Caucasian families in which the age of the origin parent and the year of conception for the first carrier/hemophiliac were available. No evidence for a paternal age effect was seen; however, an advanced maternal age effect was observed (P = 0.03) and was particularly prominent in transversions. This suggested that an increased maternal age results in a higher rate of transmitted mutations, whereas the increased number of mitotic replications associated with advanced paternal age has little, if any, effect on the rate of transmitted mutation.
Liu et al. (2000) found that the pattern of germline mutations in 66 hemophilia B patients from mainland China was similar to that in U.S. Caucasians, blacks, and Mexican Hispanics. The existence of a ubiquitous mutagen or the possibility that multiple mutagens could produce the same pattern of mutation was considered unlikely; the findings were compatible with the inference that endogenous processes predominate in germline mutations.
Ljung et al. (2001) found that the ratio of male to female mutation rates was 5:3 and that the overall mutation rate per gamete per generation was 5.4 x 10(-6).
Gerrard et al. (1993) introduced a recombinant human F9 cDNA into cultured primary human keratinocytes by means of a defective retroviral vector. In tissue culture, transduced keratinocytes were found to secrete biologically active factor IX. After transplantation of these cells into nude mice, human factor IX was detected in the bloodstream in small quantities for 1 week.
Kay et al. (2000) initiated a clinical study of intramuscular injection of an AAV vector expressing human factor IX in adults with severe hemophilia B. The study had a dose-escalation design. Assessment in the first 3 patients of safety and gene transfer and expression showed no evidence of germline transmission of vector sequences or formation of inhibitory antibodies against factor IX. By PCR and Southern blot analyses of muscle biopsies, Kay et al. (2000) found that the vector sequences were present in muscle, and demonstrated expression of factor IX by immunohistochemistry. They observed modest changes in clinical endpoints, including circulating levels of factor IX and frequency of factor IX protein infusion. The evidence of gene expression at low doses of vector suggested that dose calculations based on animal data may have overestimated the amount of vector required to achieve therapeutic levels in humans, and that the approach offered the possibility of converting severe hemophilia B to a milder form of the disease.
Manno et al. (2003) investigated the safety of intramuscular injection of a recombinant AAV (rAAV) vector expressing factor IX in patients with hemophilia B. Muscle biopsies of injection sites performed 2 to 10 months after vector administration confirmed gene transfer as evidenced by Southern blot and transgene expression as evidenced by immunohistochemical staining. However, circulating levels of factor IX were less than 2% in all cases and less than 1% in most. Manno et al. (2003) concluded that the results demonstrated the safety of intramuscular rAAV administration in humans in a manner similar to that used in mice and hemophilic dogs (Herzog et al. (1997, 1999)).
Nathwani et al. (2011) infused a single dose of a serotype-8-pseudotyped, self-complementary adenovirus-associated virus (AAV) vector expressing a codon-optimized human factor IX transgene in a peripheral vein in 6 patients with severe hemophilia B (factor IX activity less than 1% of normal values). Study participants were enrolled in 1 of 3 cohorts, with 2 participants in each group, and given a high, intermediate, or low dose of vector. Vector was administered without immunosuppressive therapy, and participants were followed for 6 to 16 months. AAV-mediated expression of factor IX at 2 to 11% of normal levels was observed in all participants. Four of the 6 discontinued prophylaxis and remained free of spontaneous hemorrhage; in the other 2, the interval between prophylactic injections was increased. Of the 2 participants who received the high dose of vector, 1 had a transient, asymptomatic elevation of serum aminotransferase levels, which was associated with the detection of AAV8-capsid-specific T cells in peripheral blood; the other had a slight increase in liver enzyme levels, the cause of which was less clear. Each of these 2 participants received a short course of glucocorticoid therapy, which rapidly normalized aminotransferase levels and maintained factor IX levels in the range of 3 to 11% of normal values.
George et al. (2017) infused a single-stranded AAV vector (known as SPK-9001) consisting of a bioengineered capsid, liver-specific promoter, and factor IX Padua (factor IX-R338L, 300746.0112) transgene at a dose of 5 x 10(11) vector genomes per kg of body weight in 10 men with hemophilia B who had factor IX coagulant activity of 2% or less of the normal value. The naturally occurring gain-of-function factor IX-R338L results in specific activity that is 8 to 12 times as high as nonmutant factor IX. No serious adverse events occurred during or after vector infusion. Vector-derived factor IX coagulant activity was sustained in all the participants, with a mean (+/- SD) steady-state factor IX coagulant activity of 33.7 +/- 18.5% (range, 14-81). On cumulative follow-up of 492 weeks among all the participants (range in individual participants, 28-78 weeks), the annualized bleeding rate was significantly reduced (mean rate, 11.1 events per year (range, 0-48) before vector administration versus 0.4 events per year (range, 0-4) after administration; p = 0.02), as was factor use (mean dose, 2908 IU per kg (range, 0-8090) before vector administration versus 49.3 IU per kg (range, 0-376) after administration; p = 0.004). After vector administration, 8 of 10 participants did not use factor, and 9 of 10 did not have bleeds. An asymptomatic increase in liver enzyme levels developed in 2 participants and resolved with short-term prednisone treatment. George et al. (2017) concluded that the transgene factor IX coagulant activity enabled the termination of baseline prophylaxis and the near elimination of bleeding and factor use.
Pipe et al. (2023) reported the results of an open-label, phase 3 study, after a 6-month lead-in of factor IX prophylaxis, of a 1-time infusion of AAV5 vector expressing the Padua factor IX variant (etranacogene dezaparvovec, 2 x 10(13) genomic copies per kg body weight) to 54 men aged 19 to 75 years (mean age 41.5 years) with hemophilia B with factor IX activity less than 2% of normal, regardless of preexisting AAV5 neutralizing antibodies. The annualized bleeding rate decreased from 4.19 (95% CI, 3.22-5.45) during the lead-in period to 1.51 (95% CI, 0.81-2.82) during months 7 through 18 after treatment, for a rate ratio of 0.36, demonstrating superiority of the gene therapy compared with the factor IX prophylaxis. Factor IX activity had increased from baseline by a mean of 36.2 percentage points (95% CI, 31.4 to 41.0) at 6 months and 34.3 percentage points (95% CI, 29.5 to 39.1) at 18 months after treatment. Usage of factor IX concentrate decreased by a mean of 248,825 IU per year per participant (p less than 0.001 for all comparisons). Benefits and safety were observed in participants with pretreatment AAV5 neutralizing antibody titers of less than 700. No treatment-related serious adverse events occurred.
Giannelli et al. (1983) stated that 798 cases of Christmas disease were known in the U.K., corresponding to a frequency of 1 in 30,000 males.
Connor et al. (1985), by total ascertainment, found 28 families with hemophilia B in the west of Scotland (prevalence = 1/26,870 males). Of 26 living obligate carriers, 42% were heterozygous for a TaqI polymorphism recognized by the factor IX genomic probe. Linkage disequilibrium was apparent for this RFLP and hemophilia B in the west of Scotland. This surprising finding suggested that some of these families might be related.
Soucie et al. (1998) studied the frequency of hemophilia A and hemophilia B in 6 U.S. states: Colorado, Georgia, Louisiana, Massachusetts, New York, and Oklahoma. The age-adjusted prevalence of hemophilia in all 6 states in 1994 was 13.4 cases per 100,000 males (10.5 hemophilia A and 2.9 hemophilia B). The prevalence by race/ethnicity was 13.2 cases per 100,000 white, 11.0% among African American, and 11.5% among Hispanic males. Application of age-specific prevalence rates from the 6 surveillance states to the U.S. population resulted in an estimated national population of 13,320 cases of hemophilia A and 3,640 cases of hemophilia B. For the 10-year period 1982 to 1991, the average incidence of hemophilia A and B in the 6 surveillance states was estimated to be 1 in 5,032 live male births.
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 litter mates. 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 insert could be traced through at least 5 generations and segregated with the hemophilia B phenotype.
In transgenic mice with the hemophilia B Leyden phenotype (-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 lacking the ASE failed to show the Leyden phenotype with only transient F9 expression at puberty, whereas mice with ASE showed normal and sustained 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, and 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.
Animal Studies of Gene Therapy
Busby et al. (1985) transfected baby hamster kidney (BHK) cells with a plasmid containing a gene for human factor IX and a plasmid containing a selectable marker. The cells secreted material that these authors believed to be authentic factor IX. Armentano et al. (1990) used a recombinant retroviral factor to transfer the human factor IX gene into hepatocytes from 3-week old New Zealand white rabbits. The infected cells produced human factor IX that was indistinguishable from the enzyme derived from normal human plasma.
Choo et al. (1987) introduced a full-length human factor IX cDNA containing all the natural mRNA sequences plus some flanking intron sequences combined with a metallothionein promoter. This DNA clone was microinjected into the pronuclei of fertilized murine eggs. The transgenic mice expressed high levels of mRNA, gamma-carboxylated and glycosylated protein, and biologic clotting activity that were indistinguishable from normal human plasma factor IX.
Armentano et al. (1990) used a recombinant retroviral factor to transfer the factor IX gene into hepatocytes from 3-week old New Zealand white rabbits. The infected cells produced human factor IX that was indistinguishable from the enzyme derived from normal human plasma.
Axelrod et al. (1990) demonstrated that primary skin fibroblasts from hemophilic dogs, transduced by recombinant retrovirus containing a canine factor IX cDNA, secreted high levels of biologically active canine factor IX into the medium.
Yao et al. (1991) infected rat capillary endothelial cells (CECs) with a Moloney murine leukemia virus-derived retrovirus vector that contained human factor IX cDNA. They found that a single RNA transcript of 4.4 kb, predicted by the construct, and a recombinant factor IX of 68 kD identical to purified plasma factor IX were formed. The recombinant factor IX that was produced showed full clotting activity, demonstrating that CECs have an efficient mechanism for posttranslational modifications, including gamma-carboxylation, essential for its biologic activity. These results, in addition to other properties of the endothelium, suggested that CECs could serve as an efficient drug delivery vehicle producing factor IX for somatic gene therapy of hemophilia B.
Kay et al. (1993) developed a method for hepatic gene transfer in vivo by the direct infusion of recombinant retroviral vectors into the portal vasculature, and showed that the method resulted in the persistent expression of exogenous genes. When canine factor IX cDNA was transduced directly into hepatocytes of affected dogs in vivo, the animals constitutively expressed low levels of canine factor IX for more than 5 months. Persistent expression of the clotting factor resulted in reduction of whole blood clotting time and partial thromboplastin time of the treated animals.
Wang et al. (1997) generated a mouse model in which the gene encoding factor IX was disrupted by homologous recombination. The nullizygous mice were devoid of factor IX antigen in plasma. Consistent with the bleeding disorder, the factor IX coagulant activities for wildtype, heterozygous, and homozygous mice were 92, 53, and less than 5%, respectively, in activated partial thromboplastin time assays. Plasma factor IX activity in the deficient -/- mice was restored by introducing wildtype murine factor IX gene via adenoviral vectors. Thus, these factor IX-deficient mice provided a useful animal model for gene therapy studies of hemophilia B. The factor IX-deficient mice showed extensive bleeding after clipping a portion of the tail and bled to death unless the wound was cauterized. Additionally, in contrast to the normal mice, they showed swollen extremities and extensive hemorrhagic lesions after trauma. Female homozygous -/- mice gave birth without complications.
Schnieke et al. (1997) produced transgenic sheep carrying the human factor IX gene by nuclear transfer. Ovine primary fetal fibroblasts were cotransfected with a neomycin-resistance marker gene (neo) and a human coagulation factor IX genomic construct designed for expression of the encoded protein in sheep milk. Nuclear transfer to enucleated oocytes was performed using either cloned transfectant fibroblasts or a population of neomycin-resistant cells as donors. Six transgenic lambs were liveborn: 3 produced from cloned transfectant cells contained factor IX and neo transgenes, whereas 3 produced from the uncloned population contained the marker gene only.
Preclinical studies in mice and hemophilic dogs showed that introduction of an adeno-associated viral (AAV) vector encoding blood coagulation factor IX into skeletal muscle results in sustained expression of factor IX at levels sufficient to correct the hemophilic phenotype (Herzog et al., 1997; Herzog et al., 1999).
Yant et al. (2000) described the successful use of transposon technology for the nonhomologous insertion of foreign genes into the genomes of adult mammals using naked DNA. Yant et al. (2000) showed that the 'Sleeping Beauty' transposase, the product of a synthetic transposable element, can efficiently insert transposon DNA into the mouse genome in approximately 5 to 6% of transfected mouse liver cells. Chromosomal transposition resulted in long-term expression (greater than 5 months) of human blood coagulation factor IX at levels that were therapeutic in a mouse model of hemophilia B.
Li et al. (2011) showed that zinc finger nucleases are able to induce double-strand breaks efficiently when delivered directly to mouse liver and that, when codelivered with an appropriately designed gene targeting vector, they can stimulate gene replacement through both homology-directed and homology-independent targeted gene insertion at the zinc finger nuclease-specified locus. The level of gene targeting achieved was sufficient to correct the prolonged clotting times in a mouse model of hemophilia B, and remained persistent after induced liver regeneration. Thus, Li et al. (2011) concluded that zinc finger nuclease-driven gene correction can be achieved in vivo, raising the possibility of genome editing as a viable strategy for the treatment of genetic disease.
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