Mutations in cystathionine β-synthase or methylenetetrahydrofolate reductase gene increase N-homocysteinylated protein levels in humans

Hieronim Jakubowski, Godfried H J Boers, Kevin A. Strauss

Research output: Contribution to journalArticle

70 Scopus citations

Abstract

Severely elevated plasma homocysteine (Hcy) levels observed in genetic disorders of Hcy metabolism are associated with pathologies in multiple organs and lead to premature death due to vascular complications. In addition to elevating plasma Hcy, mutations in cystathionine β-synthase (CBS) or methylenetetrahydrofolate reductase (MTHFR) gene lead to markedly elevated levels of circulating Hcy-thiolactone. The thiooester chemistry of Hcy-thiolactone underlies its ability to form isopeptide bonds with protein lysine residues (N-Hcy-protein), which may impair or alter the protein's function. However, it was not known whether genetic deficiencies in Hcy metabolism affect N-Hcy-protein levels in humans. Here we show that plasma N-Hcy-protein levels are significantly elevated in CBS-and MTHFR-deficient patients. We also show that CBS-deficient patients have significantly elevated plasma levels of prothrombotic N-Hcy-fibrinogen. These results provide a possible explanation for increased atherothrombosis observed in CBS-deficient patients.

Original languageEnglish (US)
Pages (from-to)4071-4076
Number of pages6
JournalFASEB Journal
Volume22
Issue number12
DOIs
StatePublished - Dec 1 2008

All Science Journal Classification (ASJC) codes

  • Genetics
  • Molecular Biology
  • Biochemistry
  • Biotechnology

Keywords

  • Atherothrombosis
  • Fibrinogen
  • Genetic hyperhomocysteinemia
  • Homocysteine thiolactone

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