MICE DEFICIENT IN CYSTATHIONINE BETA-SYNTHASE - ANIMAL-MODELS FOR MILD AND SEVERE HOMOCYST(E)INEMIA

Studies by various investigators have indicated that elevated levels o f plasma homocyst(e)ine are strongly associated with the occurrence of occlusive vascular diseases, With the eventual aim of determining whe ther 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 i n mouse embryonic stem cells was used to inactivate the cystathionine beta-synthase [L-serine hydrolyase (adding homocysteine), EC 4.2.1.22] gene, Homozygous mutants completely lacking cystathionine beta-syntha se were born at the expected frequency from matings of heterozygotes, but they suffered from severe growth retardation and a majority of the m died within 5 weeks after birth, Histological examination showed tha t the hepatocytes of homozygotes were enlarged, multinucleated, and fi lled with microvesicular lipid droplets, Plasma homocyst(e)ine levels of the homozygotes were approximate to 40 times normal, These mice, th erefore, represent a model for severe homocyst(e)inemia resulting from the complete lack of cystathionine beta-synthase, Heterozygous mutant s have approximate to 50% reduction in cystathionine beta-synthase mRN A and enzyme activity in the liver and have twice normal plasma homocy st(e)ine levels, Thus, the heterozygous mutants are promising for stud ying the in vivo role of elevated levels of homocyst(e)ine in the etio logy of cardiovascular diseases.