Hypermethioninemia leads to fatal bleeding and increased mortality in a transgenic I278T mouse model of homocystinuria

Insun Park, Linda K. Johnson, Allaura Cox, Brian R. Branchford, Jorge Di Paola, Erez M. Bublil, Tomas Majtan

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Severely elevated plasma homocysteine and methionine lead to thromboembolic events and strokes in homocystinuric (HCU) patients. Mouse models of HCU failed to exhibit prothrombotic phenotype, presumably due to lack of hypermethioninemia. We evaluated the impact of hypermethioninemia together with hyperhomocysteinemia on murineHCUphenotype and compared the efficacy of the current and novel therapies for HCU. High methionine intake decreased survival of I278T mice, which died from intestinal bleeding with hepatic and pancreatic failure. I278T mice on normal or increased methionine intake developed endothelial dysfunction, but paradoxically demonstrated delayed occlusion in an induced arterial thrombosis model. RNA-seq analysis suggested that expression of coagulation factor XI (FXI) is downregulated in livers of I278T mice. Indeed, plasma concentrations of FXI were decreased in I278T mice on normal diet and further reduced by increased methionine intake. Dietary methionine restriction normalized the observed phenotype. Similarly, treatment with OT-58, a novel enzyme therapy for HCU, corrected the phenotype in I278T mice regardless of their dietary methionine intake. Hypermethioninemia does not contribute to prothrombotic phenotype in murine HCU. Downregulation of FXI may contribute to the lack of prothrombotic tendency in I278T mice. Methionine restriction or treatment with OT-58 corrects vascular disease in the I278T mouse model of HCU.

Original languageEnglish
Article number244
JournalBiomedicines
Volume8
Issue number8
DOIs
StatePublished - Aug 2020

Keywords

  • Bleeding
  • Coagulation factors
  • Homocysteine
  • Homocystinuria
  • Methionine intake
  • Thrombosis

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