Noncoding sequence variants define a novel regulatory element in the first intron of the N-acetylglutamate synthase gene.
Noncoding sequence variants define a novel regulatory element in the first intron of the N-acetylglutamate synthase gene.
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DOI：
10.1002/humu.24281
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发表时间：
2021-12
期刊：
影响因子：
3.9
通讯作者：
Caldovic L
中科院分区：
文献类型：
--
作者：
Häberle J;Moore MB;Haskins N;Rüfenacht V;Rokicki D;Rubio-Gozalbo E;Tuchman M;Longo N;Yandell M;Andrews A;AhMew N;Caldovic L
n -乙酰谷氨酸合成酶缺乏症（NAGSD, MIM #237310）是一种常染色体隐性尿素循环疾病，由NAGS基因表达减少或NAGS酶缺陷导致n -乙酰谷氨酸（NAG）的产生减少引起，NAG是氨甲酰磷酸合成酶1 （CPS1）的变乙酰激活剂。NAGSD是唯一一种可以用单一药物有效治疗的尿素循环障碍，n -氨甲酰谷氨酸（n -氨甲酰谷氨酸，NCG）是一种稳定的NAG类似物，可以激活CPS1恢复尿素生成。我们描述了3例由于NAGS调控区域的4个新的非编码序列变异而导致的NAGSD患者。所有三例患者均有高氨血症，经NCG治疗后消失。序列变体NM_153006.2:c。427-222G >A和NM_153006.2:c。427-218A >C位于NAGS的第一个547bp长的内含子中，定义了一个结合视黄酸X受体α的新的NAGS调控元件。序列变体NC_000017.10:g。42078967A>T （NM_153006.2:c.−3065A >t）和NC_000017.10:g。42078934C>T （NM_153006.2:c. - 3098C>T）分别位于已知的HNF1和预测的糖皮质激素受体结合位点内的NAGS增强子中。HepG2和HuH-7细胞的报告基因检测表明，这四种替换均可导致NAGS的表达降低。这些发现表明，分析NAGS和其他尿素循环基因的非编码区可以揭示疾病的分子原因，并确定新的尿素发生调节因子。
N-acetylglutamate synthase deficiency (NAGSD, MIM #237310) is an autosomal recessive urea cycle disorder caused either by decreased expression of the NAGS gene or defective NAGS enzyme resulting in decreased production of N-acetylglutamate (NAG), an allosteric activator of carbamylphosphate synthetase 1 (CPS1). NAGSD is the only urea cycle disorder that can be effectively treated with a single drug, N-carbamylglutamate (NCG), a stable NAG analog, which activates CPS1 to restore ureagenesis. We describe three patients with NAGSD due to four novel non-coding sequence variants in the NAGS regulatory regions. All three patients had hyperammonemia that resolved upon treatment with NCG. Sequence variants NM_153006.2:c.427–222G>A and NM_153006.2:c.427–218A>C reside in the 547 bp long first intron of NAGS and define a novel NAGS regulatory element that binds retinoic X receptor α. Sequence variants NC_000017.10:g.42078967A>T (NM_153006.2:c.−3065A>T) and NC_000017.10:g.42078934C>T (NM_153006.2:c.−3098C>T) reside in the NAGS enhancer, within known HNF1 and predicted glucocorticoid receptor binding sites, respectively. Reporter gene assays in HepG2 and HuH-7 cells demonstrated that all four substitutions could result in reduced expression of NAGS. These findings show that analyzing non-coding regions of NAGS and other urea cycle genes can reveal molecular causes of disease and identify novel regulators of ureagenesis.
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影响因子：
1.9
作者：
Al Kaabi EH;El-Hattab AW
通讯作者：
El-Hattab AW
影响因子：
5.3
作者：
Christoffels, VM;Grange, T;Lamers, WH
通讯作者：
Lamers, WH
影响因子：
4.2
作者：
Esteban-Pretel, Guillermo;Pilar Marin, M.;Barber, Teresa
通讯作者：
Barber, Teresa
DOI：
10.1016/s0006-291x(02)02696-7
发表时间：
2002-12-13
影响因子：
3.1
作者：
Caldovic, L;Morizono, H;Tuchman, M
通讯作者：
Tuchman, M
影响因子：
4.8
作者：
Christoffels, VM;Habets, PEMH;Lamers, WH
通讯作者：
Lamers, WH