Neural tube defects induced by folate deficiency in mutant curly tail (Grhl3) embryos are associated with alteration in folate one-carbon metabolism but are unlikely to result from diminished methylation.
Neural tube defects induced by folate deficiency in mutant curly tail (Grhl3) embryos are associated with alteration in folate one-carbon metabolism but are unlikely to result from diminished methylation.
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DOI：
10.1002/bdra.20690
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发表时间：
2010-08
影响因子：
--
通讯作者：
Greene, Nicholas D. E.
中科院分区：
文献类型：
--
作者：
De Castro, Sandra C. P.;Leung, Kit-yi;Sayery, Dawn;Burren, Katie;Rozen, Rima;Copp, Andrew J.;Greene, Nicholas D. E.
叶酸一碳代谢已被认为是神经管缺陷（NTD）易感性的决定因素，这是由于母体叶酸补充剂的预防作用以及与叶酸水平降低标志物相关的较高风险。叶酸一碳代谢比较卷曲尾（ct/ct）和遗传匹配的同源（+ct/+ct）小鼠品系使用脱氧尿苷抑制试验在胚胎成纤维细胞和定量的S-腺苷甲硫氨酸（SAM）和S-腺苷高半胱氨酸（SAH）在胚胎中使用液相色谱串联质谱。通过产生复合突变体胚胎，研究了卷曲尾和5，10-亚甲基四氢叶酸还原酶（MTHFR）无效等位基因之间可能的遗传互作。ct/ct细胞中胸苷酸合成无缺陷，但外源性胸苷掺入量低于+ct/+ct细胞。在+ct/+ct胚胎中，SAM/SAH比率因膳食叶酸缺乏而降低，并通过叶酸或肌醇治疗恢复正常，与NTDs的预防相关。与此相反，叶酸缺乏导致SAM/SAH比率显着增加在ct/ct胚胎。卷曲尾胚胎中MTHFR功能的丧失显著降低了SAM/SAH比率，但没有引起头部NTDs或改变尾部NTDs的频率。卷尾成纤维细胞和胚胎，其中Grhl 3的表达减少，显示在一碳代谢的改变，特别是在叶酸缺乏症的反应，与遗传匹配的同类对照，其中Grhl 3是不受影响的。然而，与叶酸缺乏不同，甲基化潜力降低似乎不足以引起卷尾品系的头部NTD，也不会增加尾部NTD的频率。
Folate one-carbon metabolism has been implicated as a determinant of susceptibility to neural tube defects (NTDs), owing to the preventive effect of maternal folic acid supplementation and the higher risk associated with markers of diminished folate status. Folate one-carbon metabolism was compared in curly tail (ct/ct) and genetically matched congenic (+ct/+ct) mouse strains using the deoxyuridine suppression test in embryonic fibroblast cells and by quantifying s-adenosylmethionine (SAM) and s-adenosylhomocysteine (SAH) in embryos using liquid chromatography tandem mass spectrometry. A possible genetic interaction between curly tail and a null allele of 5,10-methylenetetrahydrofolate reductase (MTHFR) was investigated by generation of compound mutant embryos. There was no deficit in thymidylate biosynthesis in ct/ct cells but incorporation of exogenous thymidine was lower than in +ct/+ct cells. In +ct/+ct embryos the SAM/SAH ratio was diminished by dietary folate deficiency and normalised by folic acid or myor-inositol treatment, in association with prevention of NTDs. In contrast, folate deficiency caused a significant increase in SAM/SAH ratio in ct/ct embryos. Loss of MTHFR function in curly tail embryos significantly reduced the SAM/SAH ratio but did not cause cranial NTDs or alter the frequency of caudal NTDs. Curly tail fibroblasts and embryos, in which Grhl3 expression is reduced, display alterations in one-carbon metabolism, particularly in the response to folate deficiency, compared with genetically-matched congenic controls in which Grhl3 is unaffected. However, unlike folate deficiency, diminished methylation potential appears to be insufficient to cause cranial NTDs in the curly tail strain, and neither does it increase the frequency of caudal NTDs.
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DOI：
10.1016/j.devbrainres.2005.06.002
发表时间：
2005-08-08
期刊：
DEVELOPMENTAL BRAIN RESEARCH
影响因子：
--
作者：
Afman, LA;Blom, HJ;van Straaten, HW
通讯作者：
van Straaten, HW
影响因子：
3.5
作者：
Chen, ZT;Karaplis, AC;Rozen, R
通讯作者：
Rozen, R
DOI：
10.1002/bdra.20223
发表时间：
2006-01-01
影响因子：
--
作者：
Li, DQ;Pickell, L;Rozen, R
通讯作者：
Rozen, R
影响因子：
3.5
作者：
Dunlevy, Louisa P. E.;Burren, Katie A.;Greene, Nicholas D. E.
通讯作者：
Greene, Nicholas D. E.
影响因子：
56.9
作者：
Fleming, A;Copp, AJ
通讯作者：
Copp, AJ