Molecular basis of hemophilia B: a defective enzyme due to an unprocessed propeptide is caused by a point mutation in the factor IX precursor

Proc Natl Acad Sci U S A. 1986 Aug;83(16):5803-7. doi: 10.1073/pnas.83.16.5803.


A mutant factor IX, designated factor IXCambridge, was isolated from a patient with hemophilia B. This protein includes an 18-residue propeptide attached to the NH2 terminus of factor IX. A point mutation at residue -1, from an arginine to a serine, precludes cleavage of the propeptide by a processing protease and interferes with gamma-carboxylation of the factor IX, indicating the importance of the leader sequence in substrate recognition by the vitamin K-dependent carboxylase. This represents an example of an enzyme defect due to the presence of a point mutation in a precursor protein (preproenzyme) that is the cause of a human hereditary disease. This defect will serve as a prototype for understanding the molecular basis of some forms of hemophilia and other hereditary enzyme deficiencies.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • DNA / analysis
  • Factor IX / genetics*
  • Factor IX / metabolism
  • Hemophilia A / blood
  • Hemophilia A / genetics*
  • Humans
  • Kinetics
  • Mutation*
  • Phospholipids / blood
  • Protein Binding
  • Protein Conformation
  • Protein Precursors / genetics*
  • Protein Precursors / metabolism


  • Phospholipids
  • Protein Precursors
  • factor IX Cambridge
  • Factor IX
  • DNA