PHYSIOLOGICAL ROLES OF THE CYSTEINE BIOSYNTHETIC PATHWAY AND PATHOSIS INDUCED BY ITS DYSFUNCTION

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Cystathionine β-synthase-deficient mice (Cbs-/- ) exhibit several pathophysiological features similar to hyperhomocysteinemic patients, including endothelial dysfunction and hepatic steatosis. Heterozygous mutants (Cbs^<+/-> ) on the C57BL/6J background are extensively analyzed in laboratories worldwide; however, detailed analyses of Cbs^<-/-> have been hampered by the fact that they rarely survive past the weaning age probably due to severe hepatic dysfunction. We backcrossed the mutants with four inbred strains (C57BL/6J(Jcl), BALB/cA, C3H/HeJ, and DBA/2J) for seven generations, and compared Cbs^<-/-> phenotypes among the different genetic backgrounds. Although Cbs^<-/-> on all backgrounds were hyperhomocysteinemic/hypermethioninemic and suffered from lipidosis/hepatic steatosis at 2 weeks of age, >30% of C3H/HeJ-Cbs^<-/-> survived over 8 weeks whereas none of DBA/2J-Cbs^<-/-> survived beyond 5 weeks. At 2 weeks, serum levels of total homocysteine and triglyceride were lowest in C3H/HeJ-Cbs^<-/->. Adult C3H/HeJ-Cbs^<-/-> survivors showed hyperhomocysteinemia but escaped hypermethioninemia, lipidosis, and hepatic steatosis. They appeared normal in general behavioral tests but showed cerebellar malformation and impaired learning ability in the passive avoidance step-through test, and required sufficient dietary supplementation of cyst(e)ine for survival, demonstrating the essential roles of cystathionine b-synthase in the central nervous system function and cysteine biosynthesis. Our C3H/HeJ-Cbs^<-/-> mice could be useful tools for investigating clinical symptoms such as mental retardation and thromboembolism that are found in homocysteinemic patients.