The F9 gene encodes coagulation factor IX (FIX), a vitamin K-dependent plasma protease that participates in the intrinsic blood coagulation pathway. FIX circulates as a zymogen, and is proteolytically activated to FIXa by activated FXIa or tissue factor-bound FVIIa. After being activated, FIXa forms a complex with Ca2+ ions, membrane phospholipids and coagulation factor VIIIa to activate coagulation factor X. Mutations within F9 gene that lead to quantitative and/or qualitative deficiencies in the circulating FIX protein are associated with hemophilia B (HB), a rare X-linked, recessively transmitted bleeding disorder (White GC et al. 2001; Rallapalli PM et al. 2013; Goodeve AC 2015). The disease severity in hemophilia is classified according to the plasma procoagulant levels of FIX activity. The severe form is defined as a factor level <1% of normal, the moderate form as a factor level of 1-5%, and the mild form with a factor level >5 and <40%. Patients with severe hemophilia frequently develop hemorrhages into joints, muscles or soft tissues without any apparent cause. They can also suffer from life-threatening bleeding episodes such as intracranial hemorrhages. Persons with mild and moderate factor deficiency rarely experience spontaneous hemorrhages, and excessive bleeding mostly occurs only following trauma or in association with invasive procedures.
A wide range of different genetic alterations are spread throughout the F9 gene, including single nucleotide substitutions, small and large deletions (Rallapalli PM et al. 2013). However functional consequences of most F9 mutations are poorly studied. The Reactome event describes altered functions of HB-associated FIX variants such as reduced FIX protein secretion due to defective expression and/or processing, failed proteolysis of factor X to Xa by defective FIX and failed formation of a membrane complex in the presence of Ca2+ ions, phospholipid, and cofactor VIIIa. The annotated HB-associated FIX variants are supported with data from functional studies (Usharani P et al. 1985; Spitzer SG et al. 1990; Ludwig M et a. 1992; Kurachi S et al. 1997; Branchini A et al. 2013).