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

Abstract
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.
AuthorsNoriyuki Akahoshi, Chiho Kobayashi, Yasuki Ishizaki, Takashi Izumi, Toshiyuki Himi, Makoto Suematsu, Isao Ishii
JournalHuman molecular genetics (Hum Mol Genet) Vol. 17 Issue 13 Pg. 1994-2005 (Jul 01 2008) ISSN: 1460-2083 [Electronic] England
PMID18364386 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Amino Acids
  • Lipid A
  • Phosphatidylcholine-Sterol O-Acyltransferase
  • Cystathionine beta-Synthase
  • Cysteine
Topics
  • Amino Acids (blood)
  • Animals
  • Behavior, Animal
  • Cerebellar Diseases (enzymology, genetics, pathology, physiopathology)
  • Cystathionine beta-Synthase (genetics, metabolism)
  • Cysteine (metabolism)
  • Disease Models, Animal
  • Female
  • Humans
  • Hyperhomocysteinemia (enzymology, genetics, pathology, physiopathology)
  • Kaplan-Meier Estimate
  • Lipid A (blood)
  • Male
  • Mice
  • Mice, Inbred Strains
  • Mice, Knockout
  • Phosphatidylcholine-Sterol O-Acyltransferase (blood)
  • Species Specificity

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