Genetic background conversion ameliorates semi-lethality and permits behavioral analyses in cystathionine beta-synthase-deficient mice, an animal model for hyperhomocysteinemia

Hum Mol Genet. 2008 Jul 1;17(13):1994-2005. doi: 10.1093/hmg/ddn097. Epub 2008 Mar 25.


Cystathionine beta-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 beta-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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / blood
  • Animals
  • Behavior, Animal
  • Cerebellar Diseases / enzymology
  • Cerebellar Diseases / genetics
  • Cerebellar Diseases / pathology
  • Cerebellar Diseases / physiopathology
  • Cystathionine beta-Synthase / genetics*
  • Cystathionine beta-Synthase / metabolism*
  • Cysteine / metabolism
  • Disease Models, Animal*
  • Female
  • Humans
  • Hyperhomocysteinemia / enzymology*
  • Hyperhomocysteinemia / genetics*
  • Hyperhomocysteinemia / pathology
  • Hyperhomocysteinemia / physiopathology
  • Kaplan-Meier Estimate
  • Lipid A / blood
  • Male
  • Mice
  • Mice, Inbred Strains
  • Mice, Knockout
  • Phosphatidylcholine-Sterol O-Acyltransferase / blood
  • Species Specificity


  • Amino Acids
  • Lipid A
  • Phosphatidylcholine-Sterol O-Acyltransferase
  • Cystathionine beta-Synthase
  • Cysteine