Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 1994-2005 |
| Number of pages | 12 |
| Journal | Human Molecular Genetics |
| Volume | 17 |
| Issue number | 13 |
| DOIs | |
| Publication status | Published - 2008 Jul |
| Externally published | Yes |
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- Genetics
Cite this
Genetic background conversion ameliorates semi-lethality and permits behavioral analyses in cystathionine β-synthase-deficient mice, an animal model for hyperhomocysteinemia. / Akahoshi, Noriyuki; Kobayashi, Chiho; Ishizaki, Yasuki; Izumi, Takashi; Himi, Toshiyuki; Suematsu, Makoto; Ishii, Isao.
In: Human Molecular Genetics, Vol. 17, No. 13, 07.2008, p. 1994-2005.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Genetic background conversion ameliorates semi-lethality and permits behavioral analyses in cystathionine β-synthase-deficient mice, an animal model for hyperhomocysteinemia
AU - Akahoshi, Noriyuki
AU - Kobayashi, Chiho
AU - Ishizaki, Yasuki
AU - Izumi, Takashi
AU - Himi, Toshiyuki
AU - Suematsu, Makoto
AU - Ishii, Isao
PY - 2008/7
Y1 - 2008/7
N2 - 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.
AB - 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.
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U2 - 10.1093/hmg/ddn097
DO - 10.1093/hmg/ddn097
M3 - Article
VL - 17
SP - 1994
EP - 2005
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 13
ER -