Two novel mutations in EGF-like domains of human factor IX dramatically impair intracellular processing and secretion

Journal of Thrombosis and Haemostasis : JTH
N EnjolrasC Negrier

Abstract

We investigated the mechanisms responsible for severe factor IX (FIX) deficiency in two cross-reacting material (CRM)-negative hemophilia B patients with a mutation in the first and second epidermal growth factor (EGF) domains of FIX (C71Y and C109Y, respectively). We have determined the kinetics of mutant FIX biosynthesis and secretion in comparison with wild-type FIX (FIXwt). In transfected cells, FIXwt was retrieved as two intracellular molecular forms, rapidly secreted into the culture medium. One appeared to be correctly N-glycosylated, and corresponded to a form trafficking between the endoplasmic reticulum (ER) and Golgi apparatus. The other corresponded to the mature form, ready to be secreted, exhibiting correct N-glycosylation and sialylation. In contrast, the two mutants, FIXC71Y and FIXC109Y, were not secreted from the cells and did not accumulate intracellularly. Relative to FIXwt, they were retained longer in the ER and were only N-glycosylated. In addition, the intracellular concentration of the FIX mutants increased when ALLN, an inhibitor of cysteine proteases and of the proteasome degradation pathway, was added to the culture medium. Both the FIX mutants and FIXwt were associated in the ER with the 78-kDa gluc...Continue Reading

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Citations

Aug 7, 2008·Molecular Therapy : the Journal of the American Society of Gene Therapy·Alex H ChangMichel Sadelain
Dec 7, 2018·Haemophilia : the Official Journal of the World Federation of Hemophilia·Sandra Le QuellecAmit Nathwani
Jul 14, 2005·Haemophilia : the Official Journal of the World Federation of Hemophilia·M MitchellUNKNOWN UK Haemophilia Centre Doctors' Organization Haemophilia Genetics Laboratory Network
Nov 18, 2014·Blood Coagulation & Fibrinolysis : an International Journal in Haemostasis and Thrombosis·Hee-Jung KimHee-Jin Kim
Jun 29, 2005·American Journal of Kidney Diseases : the Official Journal of the National Kidney Foundation·Xosé M LensVicente Barrio-Lucía

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