Identification and Characterization of an Inborn Error of Metabolism Caused by Dihydrofolate Reductase Deficiency
Identification and Characterization of an Inborn Error of Metabolism Caused by Dihydrofolate Reductase Deficiency
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DOI：
10.1016/j.ajhg.2011.01.004
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发表时间：
2011-02-11
影响因子：
9.8
通讯作者：
Newman, William G.
中科院分区：
文献类型：
--
作者：
Banka, Siddharth;Blom, Henk J.;Newman, William G.
二氢叶酸还原酶（DHFR）是叶酸代谢的关键酶，也是抗肿瘤、抗微生物和抗肿瘤药物的重要作用靶点。我们描述了三个人从两个家庭的隐性遗传性代谢缺陷，其特点是巨幼细胞性贫血和/或全血细胞减少症，严重的脑叶酸缺乏症，脑四氢生物蝶呤缺乏症由于生殖错义突变DHFR，导致深刻的酶缺乏症。我们发现，脑叶酸水平，贫血和全血细胞减少症的DHFR缺乏症可以纠正治疗与亚叶酸。这种疾病的特征提供了证据DHFR和脑四氢生物蝶呤，这是必需的多巴胺，血清素和去甲肾上腺素的形成和芳香族氨基酸的羟基化代谢之间的联系。此外，这种关系提供了深入了解叶酸在神经系统疾病中的作用，包括抑郁症，阿尔茨海默病和帕金森病。
Dihydrofolate reductase (DHFR) is a critical enzyme in folate metabolism and an important target of antineoplastic, antimicrobial, and antiinflammatory drugs. We describe three individuals from two families with a recessive inborn error of metabolism, characterized by megaloblastic anemia and/or pancytopenia, severe cerebral folate deficiency, and cerebral tetrahydrobiopterin deficiency due to a germline missense mutation in DHFR, resulting in profound enzyme deficiency. We show that cerebral folate levels, anemia, and pancytopenia of DHFR deficiency can be corrected by treatment with folinic acid. The characterization of this disorder provides evidence for the link between DHFR and metabolism of cerebral tetrahydrobiopterin, which is required for the formation of dopamine, serotonin, and norepinephrine and for the hydroxylation of aromatic amino acids. Moreover, this relationship provides insight into the role of folates in neurological conditions, including depression, Alzheimer disease, and Parkinson disease.