Biallelic mutations in CAD, impair de novo pyrimidine biosynthesis and decrease glycosylation precursors
Biallelic mutations in CAD, impair de novo pyrimidine biosynthesis and decrease glycosylation precursors
复制标题
DOI：
10.1093/hmg/ddv057
复制
发表时间：
2015-06-01
影响因子：
3.5
通讯作者：
Freeze, Hudson H.
中科院分区：
文献类型：
--
作者：
Ng, Bobby G.;Wolfe, Lynne A.;Freeze, Hudson H.
在线粒体中，氨甲酰磷酸合成酶1的活性产生氨甲酰磷酸用于尿素合成，缺乏会导致高氨血症。然而，胞质氨甲酰磷酸合成酶2是CAD编码的三功能酶的一部分;没有人类疾病归因于该基因。三功能酶含有氨甲酰磷酸合成酶2（CPS 2）、天冬氨酸转氨甲酰酶（ATCase）和二氢乳清酸酶（DHOase）活性，其包括从头嘧啶生物合成所需的六个反应中的前三个。在这里，我们描述了一个人谁是复合杂合子突变在不同领域的CAD。一个突变，c.1843-1G > A，导致外显子13的框内缺失。另一个，c.6071G > A，在一个高度保守的残基上引起错义突变（p.Arg2024Gln），该残基是氨甲酰磷酸结合所必需的。代谢通量研究表明，受损的天冬氨酸通过从头合成途径掺入RNA和DNA。此外，CTP、UTP和几乎所有作为糖基化供体的UDP活化糖均减少。尿苷补充挽救了这些异常，这表明一个潜在的治疗这种新的糖基化障碍。
In mitochondria, carbamoyl-phosphate synthetase 1 activity produces carbamoyl phosphate for urea synthesis, and deficiency results in hyperammonemia. Cytoplasmic carbamoyl-phosphate synthetase 2, however, is part of a tri-functional enzyme encoded by CAD; no human disease has been attributed to this gene. The tri-functional enzyme contains carbamoyl-phosphate synthetase 2 (CPS2), aspartate transcarbamylase (ATCase) and dihydroorotase (DHOase) activities, which comprise the first three of six reactions required for de novo pyrimidine biosynthesis. Here we characterize an individual who is compound heterozygous for mutations in different domains of CAD. One mutation, c.1843-1G > A, results in an in-frame deletion of exon 13. The other, c.6071G > A, causes a missense mutation (p.Arg2024Gln) in a highly conserved residue that is essential for carbamoyl-phosphate binding. Metabolic flux studies showed impaired aspartate incorporation into RNA and DNA through the de novo synthesis pathway. In addition, CTP, UTP and nearly all UDP-activated sugars that serve as donors for glycosylation were decreased. Uridine supplementation rescued these abnormalities, suggesting a potential therapy for this new glycosylation disorder.