Mutations in genes encoding the glycine cleavage system predispose to neural tube defects in mice and humans.
Mutations in genes encoding the glycine cleavage system predispose to neural tube defects in mice and humans.
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DOI：
10.1093/hmg/ddr585
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发表时间：
2012-04-01
影响因子：
3.5
通讯作者：
Kure S
中科院分区：
文献类型：
--
作者：
Narisawa A;Komatsuzaki S;Kikuchi A;Niihori T;Aoki Y;Fujiwara K;Tanemura M;Hata A;Suzuki Y;Relton CL;Grinham J;Leung KY;Partridge D;Robinson A;Stone V;Gustavsson P;Stanier P;Copp AJ;Greene ND;Tominaga T;Matsubara Y;Kure S
神经管缺陷（NTDs），包括脊柱裂和无脑畸形，是常见的中枢神经系统出生缺陷。人类NTDs复杂的多基因病因，以及大量可能的候选基因，阻碍了努力描绘其分子基础。叶酸单碳代谢（FOCM）的功能已被认为是NTD易感性的关键决定因素。甘氨酸裂解系统（GCS）是线粒体叶酸代谢的多酶组分，因此GCS编码基因代表参与NTD的候选者。为了研究这种可能性，我们测序了NTD患者和对照组GCS基因的编码区：AMT、GCSH和GLDC。两个独特的非同义的变化被确定在AMT基因，是不存在的控制。我们还确定了一个剪接受体位点突变和五个不同的非同义变体GLDC，这被发现显着损害酶活性，并代表推定的致病突变。为了在功能上测试神经管闭合中对GCS活性的需求，我们通过AMT突变产生缺乏GCS活性的小鼠。纯合子的−/−小鼠发生NTD的频率很高。尽管补充叶酸无法预防这些NTD，但甲硫氨酸可以部分缓解。总体而言，我们的研究结果表明，GCS基因的功能缺失突变易患小鼠和人类的NTD。这些数据突出了线粒体叶酸代谢在神经管闭合中的足够功能的重要性。
Neural tube defects (NTDs), including spina bifida and anencephaly, are common birth defects of the central nervous system. The complex multigenic causation of human NTDs, together with the large number of possible candidate genes, has hampered efforts to delineate their molecular basis. Function of folate one-carbon metabolism (FOCM) has been implicated as a key determinant of susceptibility to NTDs. The glycine cleavage system (GCS) is a multi-enzyme component of mitochondrial folate metabolism, and GCS-encoding genes therefore represent candidates for involvement in NTDs. To investigate this possibility, we sequenced the coding regions of the GCS genes: AMT, GCSH and GLDC in NTD patients and controls. Two unique non-synonymous changes were identified in the AMT gene that were absent from controls. We also identified a splice acceptor site mutation and five different non-synonymous variants in GLDC, which were found to significantly impair enzymatic activity and represent putative causative mutations. In order to functionally test the requirement for GCS activity in neural tube closure, we generated mice that lack GCS activity, through mutation of AMT. Homozygous Amt−/− mice developed NTDs at high frequency. Although these NTDs were not preventable by supplemental folic acid, there was a partial rescue by methionine. Overall, our findings suggest that loss-of-function mutations in GCS genes predispose to NTDs in mice and humans. These data highlight the importance of adequate function of mitochondrial folate metabolism in neural tube closure.
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影响因子：
8
作者：
Applegarth, DA;Toone, JR;Lowry, RB
通讯作者：
Lowry, RB
影响因子：
3.5
作者：
Chen, ZT;Karaplis, AC;Rozen, R
通讯作者：
Rozen, R
影响因子：
3.8
作者：
Elmore, C. Lee;Wu, Xuchu;Matthews, Rowena G.
通讯作者：
Matthews, Rowena G.
影响因子：
56.9
作者：
Fleming, A;Copp, AJ
通讯作者：
Copp, AJ
影响因子：
4.7
作者：
Apostolidou, S.;Abu-Amero, S.;Moore, G. F.
通讯作者：
Moore, G. F.