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.
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Authors | Noriyuki Akahoshi, Chiho Kobayashi, Yasuki Ishizaki, Takashi Izumi, Toshiyuki Himi, Makoto Suematsu, Isao Ishii |
Journal | Human molecular genetics
(Hum Mol Genet)
Vol. 17
Issue 13
Pg. 1994-2005
(Jul 01 2008)
ISSN: 1460-2083 [Electronic] England |
PMID | 18364386
(Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Amino Acids
- Lipid A
- Phosphatidylcholine-Sterol O-Acyltransferase
- Cystathionine beta-Synthase
- Cysteine
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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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