Betaine rescue of an animal model with methylenetetrahydrofolate reductase deficiency
Betaine rescue of an animal model with methylenetetrahydrofolate reductase deficiency
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DOI：
10.1042/bj20030822
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发表时间：
2004-09-15
影响因子：
4.1
通讯作者：
Rozen, R
中科院分区：
文献类型：
--
作者：
Schwahn, BC;Laryea, MD;Rozen, R
MTHFR（亚甲基四氢叶酸还原酶）催化5-甲基四氢叶酸的合成，5-甲基四氢叶酸是用于高半胱氨酸再甲基化为蛋氨酸的叶酸衍生物。MTHFR的严重缺乏导致高同型半胱氨酸血症和同型半胱氨酸尿症。甜菜碱补充剂已被证明有效地改善生化异常和临床过程中，这种缺乏症的患者。MTHFR完全敲除的小鼠可作为同型胱氨酸尿症的良好动物模型;这些小鼠的出生后早期死亡是常见的，与一些具有低残留MTHFR活性的新生儿一样。我们试图拯救Mthfr-/-小鼠出生后死亡的甜菜碱补充到他们的母亲在整个怀孕和哺乳期。与来自未补充甜菜碱的母鼠的Mthfr-/-小鼠相比，甜菜碱使Mthfr-/-小鼠的死亡率从83%降低至26%，并且从出生后第1天起显著改善了体细胞发育。生物化学评价表明，甜菜碱在哺乳幼崽中的可用性较高，同型半胱氨酸的积累减少，并通过硫交换途径减少从甜菜碱补充母鼠的Mthfr-/-幼崽的肝脏和大脑的流量。我们观察到在小脑和海马的基因敲除小鼠的增殖和分化的干扰，这些变化得到改善甜菜碱补充。甜菜碱对生存和生长的巨大影响，以及MTHFR缺陷小鼠脑中生化和发育异常的部分可逆性，强调了胆碱和甜菜碱耗尽在MTHFR缺陷所致同型胱氨酸尿症发病机制中的重要作用。
MTHFR (methylenetetrahydrofolate reductase) catalyses the synthesis of 5-methyltetrahydrofolate, the folate derivative utilized in homocysteine remethylation to methionine. A severe deficiency of MTHFR results in hyperhomocysteinaemia and homocystinuria. Betaine supplementation has proven effective in ameliorating the biochemical abnormalities and the clinical course in patients with this deficiency. Mice with a complete knockout of MTHFR serve as a good animal model for homocystinuria; early postnatal death of these mice is common, as with some neonates with low residual MTHFR activity. We attempted to rescue Mthfr-/- mice from postnatal death by betaine supplementation to their mothers throughout pregnancy and lactation. Betaine decreased the mortality of Mthfr-/- mice from 83 % to 26 % and significantly improved somatic development from postnatal day 1, compared with Mthfr-/- mice from unsupplemented dams. Biochemical evaluations demonstrated higher availability of betaine in suckling pups, decreased accumulation of homocysteine, and decreased flux through the trans-sulphuration pathway in liver and brain of Mthfr-/- pups from betaine-supplemented dams. We observed disturbances in proliferation and differentiation in the cerebellum and hippocampus in the knockout mice; these changes were ameliorated by betaine supplementation. The dramatic effects of betaine on survival and growth, and the partial reversibility of the biochemical and developmental anomalies in the brains of MTHFR-deficient mice, emphasize an important role for choline and betaine depletion in the pathogenesis of homocystinuria due to MTHFR deficiency.