title: Cystathionine beta-synthase null homocystinuric mice fail to exhibit altered hemostasis or lowering of plasma homocysteine in response to betaine treatment.
abstract: Cystathionine beta-synthase (CBS) deficient homocystinuria is an inherited metabolic defect that if untreated typically results in mental retardation, thromboembolism and a range of connective tissue disturbances. A knockout mouse model has previously been used to investigate pathogenic mechanisms in classical homocystinuria (Watanabe et al., PNAS 92 (1995) 1585-1589). This mouse model exhibits a semi-lethal phenotype and the majority of mice do not survive the early neonatal period. We report here that the birth incidence of cbs (-/-) mice produced from heterozygous crosses is non-Mendelian and not significantly improved by treatment with either the Hcy lowering compound betaine or the cysteine donor N-acetylcysteine. Betaine treatment did improve survival of cbs (-/-) mice and restored fertility to female cbs (-/-) mice but did so without significantly lowering Hcy levels. Surviving cbs (-/-) mice failed to show any alteration in coagulation parameters compared to wild-type controls. Moribund cbs (-/-) mice exhibited severe liver injury and hepatic fibrosis while surviving cbs (-/-) mice although less severely affected, still exhibited a level of severe liver injury that is not found in the human disease. The hepatopathy observed in this model may offer an explanation for the failure of cbs (-/-) mice to respond to betaine or exhibit a hypercoagulative phenotype. We conclude that although this model provides useful data on the biochemical sequelae of classical homocystinuria, it does not successfully recapitulate a number of important features of the human disease and its use for studying mechanisms in homocystinuria should be treated with caution as the hepatopathy produces changes which could influence the results.
authors.affiliation: Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, United States. ken.maclean@UCdenver.edu
authors.forename: Kenneth N
authors.initials: KN
authors.lastname: Maclean
authors.forename: Jakub
authors.initials: J
authors.lastname: Sikora
authors.forename: Viktor
authors.initials: V
authors.lastname: Kožich
authors.forename: Hua
authors.initials: H
authors.lastname: Jiang
authors.forename: Lori S
authors.initials: LS
authors.lastname: Greiner
authors.forename: Eva
authors.initials: E
authors.lastname: Kraus
authors.forename: Jakub
authors.initials: J
authors.lastname: Krijt
authors.forename: Linda S
authors.initials: LS
authors.lastname: Crnic
authors.forename: Robert H
authors.initials: RH
authors.lastname: Allen
authors.forename: Sally P
authors.initials: SP
authors.lastname: Stabler
authors.forename: Milan
authors.initials: M
authors.lastname: Elleder
authors.forename: Jan P
authors.initials: JP
authors.lastname: Kraus
mesh_terms: D000111:Acetylcysteine / Q000627:therapeutic use; D000818:Animals; D001622:Betaine / Q000627:therapeutic use*; D003541:Cystathionine beta-Synthase / Q000172:deficiency*; D004195:Disease Models, Animal; D005260:Female; D006487:Hemostasis / Q000502:physiology; D006710:Homocysteine / Q000097:blood*; D006712:Homocystinuria / Q000235:genetics* / Q000473:pathology; D008099:Liver / Q000473:pathology; D008103:Liver Cirrhosis / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout
chemical_list: D006710:Homocysteine; D001622:Betaine; D003541:Cystathionine beta-Synthase; D000111:Acetylcysteine