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Gupta S , Kuhnisch J , Mustafa A , Lhotak S , Schlachterman A , Slifker MJ , Klein-Szanto A , High KA , Austin RC , Kruger WD
Mouse models of cystathionine beta-synthase deficiency reveal significant threshold effects of hyperhomocysteinemia
FASEB J. 2009 Mar;23(3) :883-93
PMID: 18987302    PMCID: PMC2653989   
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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.
Gupta, Sapna Kuhnisch, Jirko Mustafa, Aladdin Lhotak, Sarka Schlachterman, Alexander Slifker, Michael J Klein-Szanto, Andres High, Katherine A Austin, Richard C Kruger, Warren D CA06927/CA/NCI NIH HHS/United States HL16237/HL/NHLBI NIH HHS/United States Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't United States The FASEB journal : official publication of the Federation of American Societies for Experimental Biology FASEB J. 2009 Mar;23(3):883-93. Epub 2008 Nov 5.