Mouse models of cystathionine β-synthase deficiency reveal significant threshold effects of hyperhomocysteinemia.

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-1278T Cbs^-/- mice, with a mean tHcy of 296 µM. Only Tg-1278T 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 rime. Metabolic profiling of serum and liver reveals that Tg-1278T 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-adenosyl homocysteine in the liver compared to Tg-hCBS Cbs^-/- mice. RNA profiling of livers indicate that Tg-1278T 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. [ABSTRACT FROM AUTHOR]