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Thromb Haemost
DOI: 10.1055/a-2795-9292
Review Article

Molecular Mechanisms of Factor IX Signal Peptide and Propeptide Mutations Underlying Hemophilia B

Authors

  • Shixin Li

    1   College of Bioscience and Biotechnology, Yangzhou University, Yangzhou, China

  • Zhiheng Yan

    1   College of Bioscience and Biotechnology, Yangzhou University, Yangzhou, China

  • Nan Jiang

    1   College of Bioscience and Biotechnology, Yangzhou University, Yangzhou, China

  • Guomin Shen 

    2   Department of Cell Biology, School of Basic Medical Sciences, Harbin Medical University, Harbin, China

  • Zhenyu Hao

    1   College of Bioscience and Biotechnology, Yangzhou University, Yangzhou, China
    3   Affiliated Hospital, Yangzhou University, Yangzhou, Jiangsu, China

  • Jian-Ke Tie 

    4   Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States

Funding Information This work was supported by grants 82370136 (to Z.H.) and 82570180 (to G.S.) from the National Natural Science Foundation of China; grant HL131690 (to J.K.T.) from the National Institutes of Health, USA; grant BK20231333 (to Z.H.) from the Natural Science Foundation of Jiangsu Province; Jiangsu Specially-Appointed Professor Start-up Funds grant (to Z.H.); grant 2023M732983 (to S.L.) from China Postdoctoral Science Foundation and grant YZ2023245 (to Z.H.) from Yangzhou Innovation Capability Enhancement Fund/Program.
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Graphical Abstract

ABSTRACT

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.

Keywords

coagulation factor IX - hemophilia B - pathogenic mutations - signal peptide and propeptide - vitamin K-dependent carboxylation

Contributors' Statement

All authors conceived the project, wrote, edited, and revised the manuscript. All authors approved the final version of the manuscript.




Publication History

Received: 26 September 2025

Accepted: 22 January 2026

Accepted Manuscript online:
28 January 2026

Article published online:
05 February 2026

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