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In Vitro Secretion Deficits are Common Among Human Coagulation Factor XIII Subunit B Missense Mutants: Correlations with Patient Phenotypes and Molecular Models

Authors

  • Arijit Biswas,

    Corresponding author
    1. Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany
    • Correspondence to: Arijit Biswas, Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Sigmund Freud Str. 25, 53127 Bonn, Germany. E-mail: arijit.biswas@ukb.uni-bonn.de; Johannes Oldenburg, Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Sigmund Freud Str. 25, 53127 Bonn, Germany. E-mail: johannes.oldenburg@ukb.uni-bonn.de

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    • These authors contributed equally to this work.

  • Anne Thomas,

    1. Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany
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    • These authors contributed equally to this work.

  • Carville G. Bevans,

    1. Im Hermeshain, Frankfurt am Main, Germany
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    • These authors contributed equally to this work.

  • Vytautas Ivaskevicius,

    1. Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany
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  • Johannes Oldenburg

    Corresponding author
    1. Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany
    • Correspondence to: Arijit Biswas, Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Sigmund Freud Str. 25, 53127 Bonn, Germany. E-mail: arijit.biswas@ukb.uni-bonn.de; Johannes Oldenburg, Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Sigmund Freud Str. 25, 53127 Bonn, Germany. E-mail: johannes.oldenburg@ukb.uni-bonn.de

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  • Contract grant sponsors: BONFOR(University of Bonn) to AB; Novonordisk to AB and JO.

  • Communicated by John McVey

ABSTRACT

Coagulation factor XIII (FXIII) proenzyme circulates in plasma as a heterotetramer composed of two each of A and B subunits. Upon activation, the B subunits dissociate from the A subunit dimer, which gains transglutaminase activity to cross-link preformed fibrin clots increasing mechanical strength and resistance to degradation. The B subunits are thought to possess a carrier/protective function before FXIII activation. Mutations in either A or B subunits are associated with pathological patient phenotypes characterized by mild to severe bleeding. In vitro expression of FXIII B subunit (FXIIIB) missense variants in HEK293T cells revealed impaired secretion for all seven variants studied. To investigate the likely molecular environments of the missense residues, we created molecular models of individual FXIIIB Sushi domains using phylogenetically similar complement factor H Sushi domain structural templates. Assessment of the local molecular environments for the models suggested surface or buried positions for each mutant residue and possible pathological mechanisms. The in vitro expression system and in silico analytical methods and models we developed can be used to further investigate the molecular basis of FXIIIB mutation pathologies.

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