title: Mouse models of cystathionine beta-synthase deficiency reveal significant threshold effects of hyperhomocysteinemia.
abstract: Untreated cystathionine beta-synthase (CBS) deficiency in humans is characterized by extremely elevated plasma total homocysteine (tHcy>200 microM), with thrombosis as the major cause of morbidity. Treatment with vitamins and diet leads to a dramatic reduction in thrombotic events, even though patients often still have severe elevations in tHcy (>80 microM). To understand the difference between extreme and severe hyperhomocysteinemia, we have examined two mouse models of CBS deficiency: Tg-hCBS Cbs(-/-) mice, with a mean serum tHcy of 169 microM, and Tg-I278T Cbs(-/-) mice, with a mean tHcy of 296 microM. Only Tg-I278T Cbs(-/-) animals exhibited strong biological phenotypes, including facial alopecia, osteoporosis, endoplasmic reticulum (ER) stress in the liver and kidney, and a 20% reduction in mean survival time. Metabolic profiling of serum and liver reveals that Tg-I278T Cbs(-/-) mice have significantly elevated levels of free oxidized homocysteine but not protein-bound homocysteine in serum and elevation of all forms of homocysteine and S-adenosylhomocysteine in the liver compared to Tg-hCBS Cbs(-/-) mice. RNA profiling of livers indicate that Tg-I278T Cbs(-/-) and Tg-hCBS Cbs(-/-) mice have unique gene signatures, with minimal overlap. Our results indicate that there is a clear pathogenic threshold effect for tHcy and bring into question the idea that mild elevations in tHcy are directly pathogenic.
authors.affiliation: Division of Population Science, Fox Chase Cancer Center, 333 Cottman Ave., Philadelphia, PA 19111, USA.
authors.forename: Sapna
authors.initials: S
authors.lastname: Gupta
authors.forename: Jirko
authors.initials: J
authors.lastname: Kühnisch
authors.forename: Aladdin
authors.initials: A
authors.lastname: Mustafa
authors.forename: Sarka
authors.initials: S
authors.lastname: Lhotak
authors.forename: Alexander
authors.initials: A
authors.lastname: Schlachterman
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Slifker
authors.forename: Andres
authors.initials: A
authors.lastname: Klein-Szanto
authors.forename: Katherine A
authors.initials: KA
authors.lastname: High
authors.forename: Richard C
authors.initials: RC
authors.lastname: Austin
authors.forename: Warren D
authors.initials: WD
authors.lastname: Kruger
mesh_terms: D000818:Animals; D001011:Aorta / Q000473:pathology; D003541:Cystathionine beta-Synthase / Q000172:deficiency / Q000235:genetics*; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000378:metabolism; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D020022:Genetic Predisposition to Disease; D020138:Hyperhomocysteinemia / Q000097:blood / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000378:metabolism; D008136:Longevity / Q000235:genetics; D051379:Mice; D009206:Myocardium / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D010024:Osteoporosis / Q000235:genetics / Q000378:metabolism; D017510:Protein Folding
chemical_list: D003541:Cystathionine beta-Synthase