N-Acetylglutamate Synthase Deficiency Due to a Recurrent Sequence Variant in the N-acetylglutamate Synthase Enhancer Region.
N-Acetylglutamate Synthase Deficiency Due to a Recurrent Sequence Variant in the N-acetylglutamate Synthase Enhancer Region.
复制标题
由于 N-乙酰谷氨酸合酶增强子区域中的重复序列变异导致 N-乙酰谷氨酸合酶缺陷。
DOI：
10.1038/s41598-018-33457-0
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发表时间：
2018
影响因子：
4.6
通讯作者：
Caldovic,Ljubica
中科院分区：
文献类型：
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作者：
Williams,Monique;Burlina,Alberto;Rubert,Laura;Polo,Giulia;Ruijter,GeorgeJG;vandenBorn,Myrthe;Rüfenacht,Véronique;Haskins,Nantaporn;vanZutven,LauraJCM;Tuchman,Mendel;Saris,JasperJ;Häberle,Johannes;Caldovic,Ljubica
N-乙酰谷氨酸合酶缺乏症（NAGSD，MIM #237310）是尿素循环的常染色体隐性疾病，其由N-乙酰谷氨酸（NAG）的产生缺失或减少引起，所述N-乙酰谷氨酸（NAG）的产生归因于NAGS基因表达降低或NAGS酶缺陷。NAG是氨甲酰磷酸合成酶1（CPS 1）的活性所必需的，CPS 1是尿素循环的第一个限速酶。NAGSD是唯一可以用单一药物N-氨甲酰谷氨酸盐（NCG）治疗的尿素循环障碍，NCG可以激活CPS 1并完全恢复NAGSD患者的尿素生成。我们描述了一种新的序列变体NM_153006.2：c.在来自两个NAGSD家族的三名患者中发现了NAGS增强子中的3026 C> T;两名患者患有高氨血症，在用NCG治疗后消退，而第三名患者在开始NCG治疗后增加膳食蛋白质摄入。两名患者是纯合子的变异，而第三名患者有c。3026 C> T变体和包含17号染色体上的NAGS基因的部分单亲二体。C. 3026 C> T序列变异影响脊椎动物中高度保守的碱基对;该变异被几种生物信息学工具预测为有害的。在培养的HepG 2细胞中的功能测定表明，c.- 3026 C> T置换可导致NAGS基因表达降低。这些发现强调了在寻找NAGSD的分子原因时分析NAGS基因调控区的重要性。
N-acetylglutamate synthase deficiency (NAGSD, MIM #237310) is an autosomal recessive disorder of the urea cycle that results from absent or decreased production of N-acetylglutamate (NAG) due to either decreased NAGS gene expression or defective NAGS enzyme. NAG is essential for the activity of carbamylphosphate synthetase 1 (CPS1), the first and rate-limiting enzyme of the urea cycle. NAGSD is the only urea cycle disorder that can be treated with a single drug, N-carbamylglutamate (NCG), which can activate CPS1 and completely restore ureagenesis in patients with NAGSD. We describe a novel sequence variant NM_153006.2:c.-3026C > T in the NAGS enhancer that was found in three patients from two families with NAGSD; two patients had hyperammonemia that resolved upon treatment with NCG, while the third patient increased dietary protein intake after initiation of NCG therapy. Two patients were homozygous for the variant while the third patient had the c.-3026C > T variant and a partial uniparental disomy that encompassed the NAGS gene on chromosome 17. The c.-3026C > T sequence variant affects a base pair that is highly conserved in vertebrates; the variant is predicted to be deleterious by several bioinformatics tools. Functional assays in cultured HepG2 cells demonstrated that the c.-3026C > T substitution could result in reduced expression of the NAGS gene. These findings underscore the importance of analyzing NAGS gene regulatory regions when looking for molecular causes of NAGSD.