Hemophilia B is a rare inherited bleeding disorder resulting from mutations in the coagulation factor IX (factor IX) gene. While mutations in factor IX catalytic domains directly compromise clotting activity, mutations in the signal peptide and propeptide domains contribute to disease pathogenesis through more complex and indirect mechanisms. Despite not participating directly in enzymatic catalysis, the signal peptide and propeptide domains are indispensable for proper factor IX biosynthesis, structural maturation, and post-translational modifications. Research on these regions remains limited, and the precise molecular mechanisms linking mutations in the signal peptide and propeptide domains to clinical manifestations are not yet fully elucidated. In this review, we systematically catalog pathogenic mutations identified in factor IX's signal peptide and propeptide domains, organizing them by mutation types and functional consequences. We highlight how these mutations disrupt domain integrity, compromise factor IX stability, and interfere with its physiological processing. Furthermore, we discuss additional modifiers of disease severity, such as vitamin K availability, hypersensitivity to anticoagulant therapies, and inhibitor development. By integrating genetic, biochemical, and clinical perspectives, this review highlights the crucial role of factor IX's signal peptide and propeptide domains in the pathogenesis of hemophilia B and provides a foundational mechanistic framework that may inform future therapeutic development and help elucidate the molecular basis of disease heterogeneity.
Li et al. (Wed,) studied this question.