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Mouse models of cystathionine β‐synthase deficiency reveal significant threshold effects of hyperhomocysteinemia
Author(s) -
Gupta Sapna,
Kühnisch Jirko,
Mustafa Aladdin,
Lhotak Sarka,
Schlachterman Alexander,
Slifker Michael J.,
KleinSzanto Andres,
High Katherine A.,
Austin Richard C.,
Kruger Warren D.
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.08-120584
Subject(s) - cystathionine beta synthase , homocysteine , hyperhomocysteinemia , medicine , endocrinology , homocystinuria , endoplasmic reticulum , chemistry , methionine , biology , biochemistry , amino acid
Untreated cystathionine β‐synthase (CBS) deficiency in humans is characterized by extremely elevated plasma total homocysteine (tHcy>200 µΜ), 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 µΜ). 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 µΜ, and Tg‐I278T Cbs –/– mice, with a mean tHcy of 296 µΜ. 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‐adenosyl‐homocysteine 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., Kuhnisch, 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. FASEB J. 23, 883–893 (2009)