Functional Analysis of the Factor IX Epidermal Growth Factor-Like Domain Mutation Ile66Thr Associated with Mild Hemophilia B.

Karin Knobe, Kristina Persson, Elsy Sjörin, Bruno O Villoutreix, Rolf Ljung

Research output: Contribution to journalArticlepeer-review

1 Citation (SciVal)

Abstract

he present study focused on the functional role of the mutation Ile66Thr located in the N-terminal epidermal growth factor-like domain of coagulation factor IX (FIX). This mutation causes mild hemophilia B with approximately 25% FIX coagulant activity and FIX antigen levels of around 90% of normal. In the 3-dimensional structure of porcine FIXa and in the subsequent 3-dimensional model of human FIXa that we have previously developed, residue 66 is exposed to the solvent and can be replaced by many amino acids, including Thr, without affecting the major folding/stability of the molecule. This is consistent with the basically normal antigen levels observed. We found that the FIX Ile66Thr mutant was activated to a normal extent by FVIIa/TF and FXIa. However, the ability of FIX Ile66Thr to activate FX was impaired in both the presence and absence of FVIIIa, indicating that Ile66 is not directly involved in the binding of FIX to FVIIIa.
Original languageEnglish
Pages (from-to)370-375
JournalPathophysiology of Haemostasis and Thrombosis
Volume35
Issue number5
DOIs
Publication statusPublished - 2006

Subject classification (UKÄ)

  • Pediatrics
  • Medicinal Chemistry
  • Hematology

Keywords

  • mutation Ile66Thr
  • hemophilia B
  • epidermal growth factor domain
  • factor IX
  • coagulation

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