Human Molecular Genetics Advance Access published online on March 25, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn097
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Genetic background conversion ameliorates semi-lethality and permits behavioral analyses in cystathionine β-synthase-deficient mice, an animal model for hyperhomocysteinemia
1 Departments of Molecular and Cellular Neurobiology and Gunma University Graduate School of Medicine, Gunma, Japan 2 Departments of Molecular Biochemistry, Gunma University Graduate School of Medicine, Gunma, Japan 3 Department of Pharmaceutical Sciences, Musashino University, Tokyo, Japan 4 Department of Biochemistry and Integrative Medical Biology, Keio University School of Medicine, Tokyo, Japan
* To whom correspondence should be addressed at: Department of Molecular and Cellular Neurobiology, Gunma University Graduate School of Medicine, 3-39-22 Showamachi, Maebashi, Gunma 371-8511, Japan. Tel: +81 27 220 7951; Fax: +81 27 220 7955; Email: isao{at}med.gunma-u.ac.jp
Received February 5, 2008; Revised March 5, 2008; Accepted March 21, 2008
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 β-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.