Kinetic mutations in argininosuccinate synthetase deficiency: characterisation and in vitro correction by substrate supplementation

精氨琥珀酸合成酶 基质(水族馆) 体外 化学 生物化学 生物 遗传学 内分泌学 内科学 分子生物学 医学 精氨酸 精氨酸酶 生态学 氨基酸
作者
Carmen Dı́ez-Fernández,Olivia Wellauer,Claudio Gemperle,Véronique Rüfenacht,Ralph Fingerhut,Johannes Häberle
出处
期刊:Journal of Medical Genetics [BMJ]
卷期号:53 (10): 710-719 被引量:11
标识
DOI:10.1136/jmedgenet-2016-103937
摘要

Citrullinemia type 1 is an autosomal-recessive urea cycle disorder caused by mutations in the ASS1 gene and characterised by increased plasma citrulline concentrations. Of the ∼90 argininosuccinate synthetase (ASS) missense mutations reported, 21 map near the substrate (aspartate or citrulline) binding site, and thus are potential kinetic mutations whose decreased activities could be amenable to substrate supplementation. This article aims at characterising these 21 ASS mutations to prove their disease-causing role and to test substrate supplementation as a novel therapeutic approach.We used an Escherichia coli expression system to study all potentially kinetic ASS mutations. All mutant enzymes were nickel-affinity purified, their activity and kinetic parameters were measured using tandem mass spectrometry and their thermal stability using differential scanning fluorimetry. Structural rationalisation of the effects of these mutations was performed.Of the characterised mutants, 13 were totally inactive while 8 exhibited decreased affinity for aspartate and citrulline. The activity of these eight kinetic mutations could be rescued to ∼10-99% of the wild-type using high l-aspartate concentrations.Substrate supplementation raised in vitro the activity of eight citrullinemia type 1 mutations with reduced affinity for aspartate. As a direct translation of these results to the clinics, we propose to further evaluate the use of oxaloacetate, a nitrogen-free aspartate precursor and already available medical food (anti-ageing and brain stimulating, not considered as a drug by the US Food and Drug Administration), in patients with citrullinemia type 1 with decreased aspartate affinity. Although only patients with kinetic mutations would benefit, oxaloacetate could offer a safe novel treatment.
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