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首页> 美国卫生研究院文献>JIMD Reports >N‐carbamoylglutamate‐responsive carbamoyl phosphate synthetase 1 (CPS1) deficiency: A patient with a novel CPS1 mutation and an experimental study on the mutations effects
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N‐carbamoylglutamate‐responsive carbamoyl phosphate synthetase 1 (CPS1) deficiency: A patient with a novel CPS1 mutation and an experimental study on the mutations effects

机译：N-氨基甲酰谷氨酸响应性氨基甲酰磷酸合成酶1（CPS1）缺乏：一名患者患有新的CPS1突变并对该突变的影响进行了实验研究

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摘要

N‐carbamoyl‐l‐glutamate (NCG), the N‐acetyl‐l‐glutamate analogue used to treat N‐acetylglutamate synthase deficiency, has been proposed as potential therapy of carbamoyl phosphate synthetase 1 deficiency (CPS1D). Previous findings in five CPS1D patients suggest that NCG‐responsiveness could be mutation‐specific. We report on a patient with CPS1D, homozygous for the novel p.(Pro1211Arg) CPS1 mutation, who presented at 9 days of life with hyperammonemic coma which was successfully treated with emergency measures. He remained metabolically stable on merely oral NCG, arginine, and modest protein restriction. Ammonia scavengers were only added after poor dietary compliance following solid food intake at age 1 year. The patient received a liver transplantation at 3.9 years of age, having normal cognitive, motor, and quality of life scores despite repeated but successfully treated episodes of hyperammonemia. Studies using recombinantly produced mutant CPS1 confirmed the partial nature of the CPS1D triggered by the p.(Pro1211Arg) mutation. This mutation decreased the solubility and yield of CPS1 as expected for increased tendency to misfold, and reduced the thermal stability, maximum specific activity (V max; ~2‐fold reduction), and apparent affinity (~5‐fold reduction) for ATP of the purified enzyme. By increasing the saturation of the NAG site in vivo, NCG could stabilize CPS1 and minimize the decrease in the effective affinity of the enzyme for ATP. These observations, together with prior experience, support the ascertainment of clinical responsiveness to NCG in CPS1 deficient patients, particularly when decreased stability or lowered affinity for NAG of the mutant enzyme are suspected or proven.
机译：N-氨基甲酰基-1-谷氨酸（NCG）是用于治疗N-乙酰氨基甲酸酯合酶缺乏症的N-乙酰基-1-谷氨酸类似物，已被提议作为氨基甲酰磷酸合成酶1缺乏症（CPS1D）的潜在疗法。先前在五名CPS1D患者中的发现提示NCG反应性可能是突变特异性的。我们报告了一名患者，患有CPS1D，对新的p。（Pro1211Arg）CPS1突变是纯合的，该患者在生命的9天出现高氨血症性昏迷，并已通过紧急措施成功治疗。他仅口服NCG，精氨酸和适度的蛋白质限制即可保持代谢稳定。仅在1岁时摄入固体食物后，饮食中的顺应性较差后才添加氨清除剂。该患者接受了3.9岁的肝移植手术，尽管反复但成功治疗了高氨血症发作，但其认知，运动和生活质量得分均正常。使用重组产生的突变体CPS1进行的研究证实了p。（Pro1211Arg）突变触发的CPS1D的部分性质。如预期的那样，这种突变降低了CPS1的溶解度和产量，从而增加了错误折叠的趋势，并降低了其对ATP的热稳定性，最大​​比活性（V max；降低约2倍）和表观亲和力（降低约5倍）。纯化的酶。通过增加体内NAG位点的饱和度，NCG可以稳定CPS1，并最大程度降低酶对ATP的有效亲和力。这些观察结果与先前的经验一起，可确定CPS1缺乏症患者对NCG的临床反应性，尤其是在怀疑或证明了稳定性降低或突变酶对NAG的亲和力降低时。

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