title: 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.
authors: Department of Molecular and Cellular Neurobiology, Gunma University Graduate School of Medicine, Gunma, Japan.
authors: Noriyuki
authors: N
authors: Akahoshi
authors: Chiho
authors: C
authors: Kobayashi
authors: Yasuki
authors: Y
authors: Ishizaki
authors: Takashi
authors: T
authors: Izumi
authors: Toshiyuki
authors: T
authors: Himi
authors: Makoto
authors: M
authors: Suematsu
authors: Isao
authors: I
authors: Ishii
mesh_terms: D000596:Amino Acids / Q000097:blood; D000818:Animals; D001522:Behavior, Animal; D002526:Cerebellar Diseases / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D003541:Cystathionine beta-Synthase / Q000235:genetics* / Q000378:metabolism*; D003545:Cysteine / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D020138:Hyperhomocysteinemia / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D053208:Kaplan-Meier Estimate; D008050:Lipid A / Q000097:blood; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000097:blood; D013045:Species Specificity
chemical_list: D000596:Amino Acids; D008050:Lipid A; D007862:Phosphatidylcholine-Sterol O-Acyltransferase; D003541:Cystathionine beta-Synthase; D003545:Cysteine