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
N1 - Funding Information:
We would like to thank the editors M. Sacchi, Y. Li, and C. Torres-Verdín as well as V. C. F. Barbosa and another two anonymous reviewers for valuable comments and suggestions. Many thanks to the staff of GEOPHYSICS for the publication of this paper. We also appreciate helpful comments from S. Lei, S. Huang, and W. Hu on this study. Geological data on the Mariana subduction zone were provided by L. Hu. Figures in this manuscript were generated with the Generic Mapping Tools (GMT) of Paul Wessel and Walter Smith. This work is supported by the Special Projects of Geologic Surveys of Ministry of National Lands and Resources of China (GZH200900504-207), the National Natural Science Foundation of China (41404050, 41476033, U1505232, and 41210005) and the National Program on Global Change and Air-Sea Interaction, SOA (No. GASI-GEOGE-01).
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
C2 - 18364386
AN - SCOPUS:45749150751
SN - 0964-6906
VL - 17
SP - 1994
EP - 2005
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 13
ER -