Mice deficient in cystathionine β-synthase: Animal models for mild and severe homocyst(e)inemia

Masahiko Watanabe, Jesús Osada, Yasuaki Aratani, Kimberly Kluckman, Robert Reddick, M. Rene Malinow, Nobuyo Maeda

Research output: Contribution to journalArticlepeer-review

481 Scopus citations

Abstract

Studies by various investigators have indicated that elevated levels of plasma homocyst(e)ine are strongly associated with the occurrence of occlusive vascular diseases. With the eventual aim of determining whether or not elevated plasma homocyst(e)ine concentrations are directly causative of cardiovascular diseases, we have generated mice that are moderately and severely homocyst(e)inemic. Homologous recombination in mouse embryonic stem cells was used to inactivate the cystathionine/β-synthase [L-serine hydrolyase (adding homocysteine), EC 4.2.1.22] gene. Homozygous mutants completely lacking cystathionine β-synthase were born at the expected frequency from matings of heterozygotes, but they suffered from severe growth retardation and a majority of them died within 5 weeks after birth. Histological examination showed that the hepatocytes of homozygotes were enlarged, multinucleated, and filled with microvesicular lipid droplets. Plasma homocyst(e)ine levels of the homozygotes were ≃40 times normal. These mice, therefore, represent a model for severe homocyst(e)inemia resulting from the complete lack of cystathionine β-synthase. Heterozygous mutants have ≃50% reduction in cystathionine β-synthase mRNA and enzyme activity in the liver and have twice normal plasma homocyst(e)ine levels. Thus, the heterozygous mutants are promising for studying the in vivo role of elevated levels of homocyst(e)ine in the etiology of cardiovascular diseases.

Original languageEnglish (US)
Pages (from-to)1585-1589
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume92
Issue number5
DOIs
StatePublished - Feb 28 1995
Externally publishedYes

Keywords

  • gene targeting
  • homocysteine
  • homologous recombination
  • inborn errors of metabolism

ASJC Scopus subject areas

  • General

Fingerprint

Dive into the research topics of 'Mice deficient in cystathionine β-synthase: Animal models for mild and severe homocyst(e)inemia'. Together they form a unique fingerprint.

Cite this