scholarly journals The Clinical Genetics of Hemophilia B (Factor IX Deficiency)

2021 ◽  
Vol Volume 14 ◽  
pp. 445-454
Author(s):  
Connie H Miller
Keyword(s):  
Factor Ix ◽  
Hemophilia B ◽  
Clinical Genetics ◽  
Factor Ix Deficiency

Factor VII Deficiency Remains Post-Puberty Due to Point Mutation in the HNF4 Binding Site in the Coagulant Factor VII Gene.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1947-1947
Author(s):  
XingWu Zheng ◽  
Theresa M. Tidd ◽  
Donna DiMichele ◽  
Eleanor S. Pollak
Keyword(s):  
Binding Site ◽  
Point Mutation ◽  
Mutant Allele ◽  
Factor Ix ◽  
Hemophilia B ◽  
Factor Vii ◽  
Start Site ◽  
Expression Plasmid ◽  
Fvii Deficiency ◽  
Factor Ix Deficiency

Abstract A novel T to C point mutation at −60 in the gene for coagulant Factor VII results in life-long severe coagulant Factor VII deficiency in post-pubertal twin males. The clinical course of these patients provides an informative in vivo example of the regulation of expression of vitamin K-dependent clotting protein Factor VII. An analogous point mutation in the HNF4 binding site in the Factor IX gene results in the clinical phenotype Hemophilia B Leyden, a sex-linked antigen-negative Factor IX deficiency that resolves post-puberty. The affected Factor VII deficient patients have prolonged prothrombin times (46 and 52 secs), normal aPTTs and decreased FVII levels of FVII:Coagulant activity: < 1% and FVII:Antigen: < 3%. The −60 mutation, ACTTTG → ACTCTG occurs 9 base pairs before the start site of transcription and 59 bps before the before the start site of translation. The twins are compound heterozygotes and also possess a mutation in exon 8 at amino acid 348, a mutation that has previously been reported to cause FVII deficiency. Both affected individuals have recurrent target joint hemorrhage (shoulder, elbow, ankle) requiring replacement therapy 6–12 times/year. Results: Gel mobility shift assays using a radio-labeled probe spanning from −76 to −46 in the FVII promoter region demonstrate the loss of binding of transcription factor HNF-4. Transient transfection assays in HepG2 cells using 186 bps of the mutant and the wildtype promoters (−185 to +1) revealed a loss of expression with the mutant allele. Co-transfection with an HNF4 expression plasmid resulted in an increase in expression of the wildetype construct in HeLa cells, a non-hepatic cell line. However, co-transfection of the HNF4 expression plasmid failed to increase expression with the construct containing the mutant allele sequence. Conclusion: The lack of phenotypic change of the FVII:C in 19 yo twin boys provides dynamic support of the necessity of an overlapping androgen binding site in the homologous Factor IX gene as responsible for the phenotypic resolution of Factor IX deficiency (Hemophilia B Leyden) post-puberty. It is of interest that an increase in FVII:C did not occur with advancing age in FVII deficiency due to this HNF4 binding site mutation.

scholarly journals Purified factor IX using monoclonal immunoaffinity technique: clinical trials in hemophilia B and comparison to prothrombin complex concentrates

Blood ◽  
1992 ◽  
Vol 79 (3) ◽  
pp. 568-575 ◽  
Author(s):  
HC Kim ◽  
CW McMillan ◽  
GC White ◽  
GE Bergman ◽  
MW Horton ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Vitamin K ◽  
Half Life ◽  
Viral Infections ◽  
Factor Ix ◽  
Hemophilia B ◽  
Terminal Phase ◽  
Factor Ix Deficiency ◽  
In Vivo Recovery

Abstract Replacement therapy for hemophilia B (factor IX deficiency) using prothrombin complex concentrate (PCC) has been associated with serious complications of thromboembolic events and transmission of viral infections. Monoclonal antibody-purified factor IX (Mononine) provides a highly purified factor IX concentrate, while eliminating other vitamin K-dependent factors (II, VII, and X). Mononine was evaluated for in vivo recovery, half-life, and for its safety and efficacy in 10 patients with hemophilia B. The in vivo recovery of factor IX with Mononine was a 0.67 +/- 0.14 U/dL (mean +/- SD) increase per 1U/kg of infused factor IX, and the biologic half-life (t1/2), determined using the terminal phase of elimination, was 22.6 +/- 8.1 hours. Comparison of in vivo recovery of other vitamin K-dependent factors following a single infusion of either Mononine or PCC showed that, whereas Mononine infusion caused no changes in other vitamin K-dependent factors or in prothrombin activation fragment (F1+2), PCC infusion was associated with significant increases of factors II (2.7 U/dL per 1 U/dL of IX increase) and X (2.2 U/dL for 1 U/dL for 1 U/dL of IX). Patients who used Mononine as their sole therapeutic material during the 12-month period showed an excellent response in hemostasis for their bleeding episodes. Their experience with long-term use of Mononine was at least equivalent to their previous experience with PCC in the frequency and amount of factor usage. No patients developed antibody against mouse IgG or an increase in IX inhibitor during the 12-month period. These results indicate that monoclonal antibody-purified factor IX concentrate provides hemostatically effective factor IX replacement while avoiding extraneous thrombogenic substances.

scholarly journals In vivo hepatic gene therapy: complete albeit transient correction of factor IX deficiency in hemophilia B dogs.

1994 ◽  
Vol 91 (6) ◽  
pp. 2353-2357 ◽  
Author(s):  
M. A. Kay ◽  
C. N. Landen ◽  
S. R. Rothenberg ◽  
L. A. Taylor ◽  
F. Leland ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Factor Ix ◽  
Hemophilia B ◽  
Factor Ix Deficiency

scholarly journals Molecular analysis of hemophilia B in Poland: 12 novel mutations of the factor IX gene.

1999 ◽  
Vol 46 (3) ◽  
pp. 721-726 ◽  
Author(s):  
K Wulff ◽  
K Bykowska ◽  
S Lopaciuk ◽  
F H Herrmann
Keyword(s):  
Direct Sequencing ◽  
Point Mutations ◽  
Factor Ix ◽  
Hemophilia B ◽  
Heteroduplex Analysis ◽  
Missense Mutations ◽  
Nonsense Mutations ◽  
Pcr Products ◽  
Factor Ix Deficiency ◽  
High Degree

We examined the molecular basis of factor IX deficiency in 53 unrelated Polish patients with hemophilia B. Heteroduplex analysis and direct sequencing of polymerase chain reaction (PCR) products were applied to identify the gene defect. Forty-three different point mutations were detected in the factor IX gene of 47 patients. There were 29 missense mutations, 9 nonsense mutations, 4 splice site mutations and 1 point mutation in the promoter region. Twelve mutations were novel. The results of this study emphasize a very high degree of heterogeneity of hemophilia B.

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