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PubMed1998

[Four novel point mutations of factor IX gene detected by denaturing gradient gel electrophoresis].

OBJECTIVE: To identify factor IX gene mutations in patients with hemophilia B. METHODS: The coding regions, splicing junction sites and part of the 5' and 3' flanking regions of factor IX gene were screened by polymerase chain reaction (PCR) and denaturing gradient gel electrophoresis (DGGE). RESULTS: Four amplified fragments showed abnormal electrophoresis patterns, and sequencing of them demonstrated four novel point mutations including a T to G transition at nucleotide 10,380 resulting in intron 3 covering the splicing site, a A to G transition at nucleotide 30,918 resulting in a substitution of Cys for Tyr at codon 266 in exon 8, and a A to C transition at nucleotide 31,007 resulting in a substitution of Pro for Thr at codon 299 in exon 8. CONCLUSION: Detection of mutations by PCR, DGGE and sequencing was useful not only for understanding the structure function relationship of F IX, but also for the carrier detection and prenatal diagnosis.

Electrophoresis, Gel, Two-Dimensional↗
PubMed1981

Spontaneously acquired Factor IX inhibitors in childhood.

Two previously healthy children, ages 8 months and 35 months, developed spontaneous inhibitors to Factor IX. Brief illnesses of presumed viral origin preceeded hemorrhagic symptoms in both children. Cutaneous ecchymoses and traumatic soft tissue hemorrhage were the predominant clinical features in each case. Bleeding symptoms persisted for less than 3 days and laboratory evidence of Factor IX inhibition resolved within 3 weeks. One child required treatment with fresh frozen plasma and packed red blood cell transfusions. The other child received corticosteroid therapy. Given the transient nature of acquired Factor IX inhibitors in the nonhemophilic child, a conservative approach toward therapy is recommended unless life-threatening complications supervene.

Blood Transfusion↗
PubMed1993

Haemophilia B Liverpool: a new British family with mild haemophilia B associated with a -6 G to A mutation in the factor IX promoter.

We report a Lancashire family with mild haemophilia B associated with a -6 G to A mutation in the factor IX promoter. This mutation has been reported previously in Britain in one other affected family. The factor IX haplotype of these two unrelated patients was determined by PCR analysis of seven polymorphic sites within or close to the factor IX gene. This analysis involved the intragenic Msp I polymorphism which we have now located precisely to allow the design of suitable PCR primers. The haplotype of both of these patients was identical suggesting but not proving a possible common origin for the mutation.

Base Sequence↗
PubMed1988

Partial deletion by illegitimate recombination of the factor IX gene in a haemophilia B family with two inhibitor patients.

The inhibitor phenotype occurs in six haemophilia B patients in the UK and results from development of antibodies by the patients to administered factor IX. We have analysed a partial factor IX gene deletion (London 1) in a family with two inhibitor patients. The deletion results in retention of the first five exons which code for the light chain of factor IXa, and removal of 23 kb of DNA starting 704 bp 3' of the fifth exon and terminating 10.3 kb 3' of the last exon. The 5' break is at residue -113 of an Alu repeat. No significant homology exists between the 5' and 3' termini, but a 9 bp region of complementarity is found 23 bp and 60 bp from the 5' and 3' terminus, respectively. At the cloned deletion junction a new 16 bp sequence contributes a DraI site that is also found in the genomic DNA of the two patients and a heterozygous relative. The deletion is an example of illegitimate recombination and it is proposed that such deletions occur principally during DNA replication. Loss of the 3' sequences involved in the maturation of mRNA probably results in no factor IX production. Immunological studies show that the index patient's antibodies bind both to epitopes coded by deleted and by non-deleted segments of the gene.

Base Sequence↗
PubMed1990

Determination of the minimal concentrations of contact activation factors in deficient substrate plasmas required to assess accurately factor XII, factor XI, factor IX, and high molecular weight kininogen.

Using combined deficient plasmas prepared by passage of a deficient plasma over an anti-factor XI-monoclonal antibody column, we have determined the threshold concentrations of each coagulation factor of contact phase in factor-deficient substrate plasmas required to determine accurately the functional activities of factor XII, factor XI, factor IX and high molecular weight kininogen (HMWK). In order to reliably quantitate factor XI and factor IX activity levels, at least 20% factor XII and 20% factor XI, respectively, were required in the deficient substrate plasmas. In the assessment of factor XII activity, approximately 40% factor XI was required in the factor XII-deficient substrate plasma. On the other hand, only 11-12% factor XI or HMWK was required in the deficient substrate plasmas in the assessment of these two clotting factors. Our data emphasize that deficiencies of other clotting factors may reduce the apparent activity of the clotting factor in question if their concentration is rate-limiting in the clotting assay.

Blood Coagulation Disorders↗
PubMed1996

Successful expression of human factor IX following repeat administration of adenoviral vector in mice.

Adenoviral vectors can direct high-level expression of a transgene, but, due to a host immune response to adenoviral antigens, expression is of limited duration, and repetitive administration has generally been unsuccessful. Exposure to foreign proteins beginning in the neonatal period may alter or ablate the immune response. We injected adult and neonatal (immunocompetent) CD-1 mice intravenously with an adenoviral vector expressing human blood coagulation factor IX. In both groups of mice, expression of human factor IX persisted for 12-16 weeks. However, in mice initially injected as adults, repeat administration of the vector resulted in no detectable expression of the transgene, whereas in mice initially injected in the neonatal period, repeat administration resulted in high-level expression of human factor IX. We show that animals that fail to express the transgene on repeat administration have developed high-titer neutralizing antibodies to adenovirus, whereas those that do express factor IX have not. This experimental model suggests that newborn mice can be tolerized to adenoviral vectors and demonstrates that at least one repeat injection of the adenoviral vector is possible; the model will be useful in elucidating the immunologic mechanisms underlying successful repeat administration of adenoviral vectors.

Adenoviridae↗
PubMed1996

Safety and efficacy of monoclonal antibody purified factor IX concentrate in previously untreated patients with hemophilia B.

The safety and efficacy of a monoclonal antibody purified factor IX concentrate were evaluated in two continuing trials of 32 previously untreated patients with mild, moderate, or severe hemophilia B. Patients were evaluated every 2 weeks for 24 weeks and every 3 months thereafter for at least 1 year. No patients became positive for human immunodeficiency virus antibody or hepatitis C virus antibody during the trial. Two patients developed a false-positive hepatitis B core antibody, one transiently, but neither had elevated levels of alanine aminotransferase (ALT). None of the 25 patients evaluable for non-A, non-B, non-C hepatitis by strict International Society of Thrombosis and Hemostasis criteria developed elevated levels of ALT indicative of posttransfusion infection. Anaphylaxis occurred in one subject who also developed an inhibitor to factor IX (19.3 Bethesda units). Five of the eight adverse events reported (63%) were mild in severity, and the relationship of three of these to therapy was considered remote. Hemostasis with monoclonal antibody purified factor IX concentrate was excellent in all patients.

Adolescent↗
PubMed1988

Disappearance of inhibitor to factor IX in a patient with severe haemophilia B and immunological characterization of the inhibitor.

Disappearance of an inhibitor to factor IX in an 11-year-old boy with haemophilia B is described. He had been given a total of 14,200 units of a prothrombin complex concentrate (PCC) before an inhibitor to factor IX developed. He subsequently received four separate infusions of PCC and his inhibitor titre rose in response to the treatment for the following 4 years. No inhibitor is presently detected despite repeated administration of PCC. Immunological characterization of the inhibitor by inhibitor neutralization assays, modified crossed-immunoelectrophoresis and enzyme-linked immunosorbent assay demonstrated that it contained IgG2 and IgG4 heavy chains and kappa and lambda light chains. No large deletion of the factor IX gene in the patient was observed using cDNA (cVII).

Child↗
PubMed1993

Reduced coagulation activation following infusion of a highly purified factor IX concentrate compared to a prothrombin complex concentrate.

We have looked for evidence of coagulation activation in six subjects with haemophilia B by performing a single-blind active control cross-over study comparing a recently developed factor IX concentrate with a conventional prothrombin complex concentrate (PCC). Samples were obtained before infusion and at 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36 and 48 h for assay of factor IX, prothrombin time, fibrinopeptide A (FPA), prothrombin fragment F1 + 2, D-dimer, thrombin-antithrombin complexes (TAT) and antithrombin III (ATIII). Following administration of the PCC there was evidence of coagulation activation in five of the six recipients for up to 6 h after the infusion. The factor IX concentrate induced a moderate degree of coagulation activation in one subject. There was no significant difference between the two products in respect of either recovery or half-life. This study provides further evidence that the new high purity preparations of factor IX concentrates produce significantly less coagulation activation than currently available PCCs. It remains to be established whether this will result in a corresponding reduction in thromboembolic complications in clinical use.

Adolescent↗
PubMed2000

Structural analysis of N-linked sugar chains of human blood clotting factor IX.

The structures of N-glycans of human blood clotting factor IX were studied. N-Glycans liberated by hydrazinolysis were N-acetylated and the reducing-end sugar residues were tagged with 2-aminopyridine. The pyridylamino (PA-) sugar chains thus obtained were purified by HPLC. Each PA-sugar chain was analyzed by two-dimensional sugar mapping combined with glycosidase digestion. The major structures of the N-linked sugar chains of human factor IX were found to be sialotetraantennary and sialotriantennary chains with or without fucose residues. These highly sialylated sugar chains are located on the activation peptide of the protein.

Carbohydrate Sequence↗
PubMed1992

Haplotype analysis of identical factor IX mutants using PCR.

We have detected the mutations in the factor IX genes from all of the haemophilia B patients registered at Malmö haemophilia centre and are currently examining the entire UK haemophilia B population. From these studies we have found 13 base substitutions which have recurred in 1-6 other, presumably unrelated, patients. In order to determine the minimum number of independent repeats of each mutation we have used PCR to examine the five factor IX polymorphisms forming the most informative combinations and we have characterised the haplotype of each patient. Patients with different haplotypes are assumed to be unrelated and thus to carry independent mutations. All but one of the 13 mutations occur in at least 2 haplotypes thus pinpointing 12 mutational hotspots and mutations that can be clearly considered detrimental. Two of the 13 substitutions occur at non-CpG sites.

Amino Acid Sequence↗
PubMed2004

Molecular characterization of hemophilia B in North Indian families: identification of novel and recurrent molecular events in the factor IX gene.

BACKGROUND AND OBJECTIVES: Hemophilia B is an X-linked recessive, bleeding disorder caused by mutations in the factor IX gene. A wide range of mutations, showing large molecular heterogeneity, has been described in hemophilia B patients. Our study was aimed at characterizing mutations in the factor IX gene in a cohort of North Indian hemophilia B patients. DESIGN AND METHODS: Polymerase chain reaction (PCR) amplification and direct sequencing of all regions of likely functional significance- the coding regions, promoter, the 5' UTR, the splice junctions and parts of the 3' UTR of the factor IX gene was done in 18 families carrying a severe form of hemophilia B. RESULTS: We identified 10 point mutations (including 2 novel ones); one novel deletion and one donor splice site mutation. Recurrence of a nonsense and a missense mutation was observed. The mutation in 3 families could not be characterized. None of the 14 polymorphic positions reported in the Haemophilia B Mutation database in the regions sequenced were polymorphic; herein we report four novel synonymous single base mismatches. One mutation reported to be causative in the database was found to be more likely a non-causal polymorphism. INTERPRETATION AND CONCLUSIONS: Our data confirm the remarkable heterogeneity of the mutational spectrum in hemophilia B among affected families. This is the first mutation report on the disease in the Indo-Aryan population from the Indian subcontinent. Identification of a causative mutation leads to more precise carrier detection than does conventional polymorphism-based linkage analysis. This can effectively be used to establish genotype/ phenotype relationships.

Amino Acid Substitution↗
PubMed1996

Stabilization of transgene expression by incorporation of E3 region genes into an adenoviral factor IX vector and by transient anti-CD4 treatment of the host.

Complex interactions between replication deficient adenoviral vectors (Ad5) and the immune system of the host influence the stability of transgenes in vivo. Vector-infected cells are attacked by diverse cellular immune mechanisms which limit transgene persistence. On the other hand, the products of several E3 region genes of wild-type adenovirus can suppress host immune reactions by interference with the expression of MHC class I molecules and by other mechanisms. We have developed an adenoviral vector for human factor IX (Ad5E3+FIX) which carries the E3 region of wild-type adenovirus, and an E3-deleted vector of otherwise similar structure (ad5 delta E3FIX). Intravenous injection of Ad5E3+FIX in C57BI/6 mice resulted in expression levels up to 6000 ng/ml of recombinant human factor IX in the mouse plasma and in enhanced transgene stability as compared with the vector Ad5 delta E3FIX. Whereas expression from E3-deleted vectors was essentially turned off 8 weeks after the gene transfer, the vector Ad5E3+FIX3+FIX supported transgene expression with therapeutic levels of human factor IX in the mouse plasma for > 4 months. The enhanced stability of the vector Ad5E3+FIX appears to be a consequence of efficient E3 region-mediated suppression of the host's antivector immune response. As an additional approach to improving transgene stability the influence of transient CD4+ T cell depletion of the host was investigated. CD4+ cytotoxic T lymphocytes contribute to the clearance of adenovirus-infected cells and play a pivotal role in the activation of CD8+ cytotoxic T cells and as helper T cells in the formation of human adenovirus neutralizing antibodies (HANA). Transient anti-CD4 treatment of the host limited to the time of vector injection resulted in a significant prolongation of transgene expression from the factor IX vector Ad5E3+FIX and a luciferase vector Ad5Luc. The combination of transient anti-CD4 treatment of the host and integration of a complete E3 region in an adenoviral vector resulted in markedly improved transgene stability after gene transfer to the liver (therapeutic factor IX levels for > 6 months).

Adenoviridae↗
PubMed1985

[Articular and muscular hemorrhages in hemophilia A with anti-factor VIII antibodies. Treatment with selected batches of PPSB (factor IX concentrate)].

Over a 10-month period, 65 bleeding episodes in 14 hemophilia A patients with anti-Factor VIII antibodies were treated with a non-activated Factor IX concentrate (PPSB). A single dose of 58-102 U/kg of Factor IX (average 80 U/kg) was used in 51 hemarthroses, 13 muscle hematomas and one dental bleed. Overall clinical results were satisfactory in 51% of cases. Forty nine per cent of acute hemarthroses were clinically improved. Safety tests were unchanged and no significant elevation of anti-VIII: C titers was recorded. These preliminary results ae similar to those obtained with single doses of activated prothrombin complex concentrates given to the same patients (Autoplex and FEIBA).

Adolescent↗