Untreated cystathionine β-synthase (CBS) deficiency in humans is characterized by extremely elevated plasma total homocysteine (tHcy>200 μM), 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 μM). 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 μM, and Tg-I278T Cbs−/− mice, with a mean tHcy of 296 μM. 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, S., Kühnisch, J., Mustafa, A., Lhotak, S., Schlachterman, A., Slifker, M. J., Klein-Szanto, A., High, K. A., Austin, R. C., Kruger, W. D. Mouse models of cystathionine β-synthase deficiency reveal significant threshold effects of hyperhomocysteinemia
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