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

Noriyuki Akahoshi, Chiho Kobayashi, Yasuki Ishizaki, Takashi Izumi, Toshiyuki Himi, Makoto Suematsu, Isao Ishii

Research output: Contribution to journalArticle

38 Citations (Scopus)

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 languageEnglish
Pages (from-to)1994-2005
Number of pages12
JournalHuman Molecular Genetics
Volume17
Issue number13
DOIs
Publication statusPublished - 2008 Jul
Externally publishedYes

Fingerprint

Cystathionine
Hyperhomocysteinemia
Animal Models
Lipidoses
Liver
Aptitude
Thromboembolism
Homocysteine
Dietary Supplements
Weaning
Exercise Test
Intellectual Disability
Cysteine
Survivors
Cysts
Triglycerides
Central Nervous System
Learning
Phenotype
Survival

ASJC Scopus subject areas

  • Genetics

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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. / 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 journalArticle

Akahoshi, Noriyuki ; Kobayashi, Chiho ; Ishizaki, Yasuki ; Izumi, Takashi ; Himi, Toshiyuki ; Suematsu, Makoto ; Ishii, Isao. / Genetic background conversion ameliorates semi-lethality and permits behavioral analyses in cystathionine β-synthase-deficient mice, an animal model for hyperhomocysteinemia. In: Human Molecular Genetics. 2008 ; Vol. 17, No. 13. pp. 1994-2005.
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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.",
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