Factor IX – Hemophilia B

Factor IX (F9) is an X-linked gene encoding a vitamin K–dependent serine protease essential for the intrinsic coagulation cascade. Hemophilia B (MONDO:0010604), also known as Christmas disease, arises from deficiency or dysfunction of factor IX, leading to prolonged activated partial thromboplastin time and bleeding diathesis (HP:0003645, HP:0001892).

Extensive molecular analyses have identified >1113 unique F9 variants in 3721 hemophilia B patients, including missense, nonsense, splice-site, promoter, and deep intronic changes (PMID:23617593). X-linked recessive inheritance is confirmed by co-segregation of pathogenic F9 variants in >77 kindreds (PMID:11328285).

Recurrent and founder mutations include the c.223C>T (p.Arg75Ter) nonsense allele in Amish, German, and other populations (PMID:1864609); promoter region variants such as –6G>A and –20T>A causing the Leyden phenotype (PMID:8478007, PMID:1631121); and deep intronic substitutions like c.278-1806A>C uncovered by whole-gene sequencing (PMID:36696202).

Functional studies demonstrate that loss-of-function variants disrupt FIX transcription, post-translational processing, activation by Factor XIa and VIIa–TF, calcium binding, EGF domain folding, and interaction with cofactor FVIIIa. For example, the c.10401C>A (p.Gln50Pro) variant abolishes enzymatic activity and markedly delays activation by Factor XIa (PMID:2306516).

In vitro and in vivo models, including recombinant variants and CRISPR/Cas9-mediated correction of c.947T>C (p.Ile316Thr) in patient-derived iPSCs and murine knock-in models, have restored FIX function and hemostasis, reinforcing haploinsufficiency as the pathogenic mechanism (PMID:26964564, PMID:37076593).

Comprehensive F9 genetic testing supports carrier detection, prenatal diagnosis, and risk assessment for inhibitor development, enabling personalized management. Key take-home: early molecular diagnosis of F9 variants underpins targeted intervention and gene-based therapies in hemophilia B.

References

• Journal of Thrombosis and Haemostasis • 2013 • An interactive mutation database for human coagulation factor IX provides novel insights into the phenotypes and genetics of hemophilia B PMID:23617593
• British Journal of Haematology • 2001 • Haemophilia B mutations in Sweden: a population-based study of mutational heterogeneity PMID:11328285
• Human Genetics • 1991 • T296----M, a common mutation causing mild hemophilia B in the Amish and others: founder effect, variability in factor IX activity assays, and rapid carrier detection PMID:1864609
• Human Genetics • 1993 • Nucleotide substitutions at the -6 position in the promoter region of the factor IX gene result in different severity of hemophilia B Leyden: consequences for genetic counseling PMID:8478007
• Proceedings of the National Academy of Sciences of the United States of America • 1992 • Disruption of a binding site for hepatocyte nuclear factor 4 results in hemophilia B Leyden PMID:1631121
• Blood • 1990 • Factor IX New London: substitution of proline for glutamine at position 50 causes severe hemophilia B PMID:2306516
• EMBO Molecular Medicine • 2016 • CRISPR/Cas9-mediated somatic correction of a novel coagulator factor IX gene mutation ameliorates hemophilia in mouse PMID:26964564
• Communications Medicine • 2023 • PAM-flexible Cas9-mediated base editing of a hemophilia B mutation in induced pluripotent stem cells PMID:37076593
• Journal of Thrombosis and Haemostasis • 2023 • Whole F9 gene sequencing identified deep intronic variations in genetically unresolved hemophilia B patients PMID:36696202

Evidence Based Scoring (AI generated)