Berning Christoph, Bieger Iris, Pauli Silke, Vermeulen Tim, Vogl Thomas, Rummel Till, Höhne Wolfgang, Koch Hans Georg, Rolinski Boris, Gempel Klaus, Häberle Johannes
Universitätsklinikum Münster, Klinik und Poliklinik für Kinder- und Jugendmedizin, Münster, Germany.
Hum Mutat. 2008 Oct;29(10):1222-7. doi: 10.1002/humu.20784.
Mild citrullinemia is an allelic variant of classical citrullinemia type I also caused by deficiency of the urea cycle enzyme argininosuccinate synthetase (ASS). Affected patients comprise a biochemical but no clinical phenotype. However, there is no reliable parameter allowing conclusions regarding the course of the disorder or its type of manifestation. The aim of this study was to test the importance of varying levels of ASS residual activities for the severity at diagnosis. Bacterial in vitro expression studies allowed the enzymatic analysis of purified wild-type and the mutant ASS proteins p.Ala118Thr (c.352G>A), p.Trp179Arg (c.535T>C), p.Val263Met (c.787G>A), p.Arg265Cys (c.793C>T), p.Met302Val (c.904A>G), p.Gly324Ser (c.970G>A), p.Gly362Val (c.1085G>T), and p.Gly390Arg (c.1168G>A). In the chosen system, classical mutations do not show any significant enzymatic activity, whereas mutations associated with a mild course yield significant ASS activity levels. The mutation p.Ala118Thr (c.352G>A) impresses by a high residual activity (62%) but a severe reduction of affinity toward the substrates citrulline and aspartate. This mutation was identified in a hitherto healthy female adult with no history of known citrullinemia who had died during the postpartum period from hyperammonemic coma. The results of this study suggest that even a high level of residual ASS activity is not a reliable prognostic marker for an uneventful clinical course. Determination of ASS residual activities, therefore, cannot help in anticipating the risk of metabolic derangement. This study should guide clinicians as well as patients with mild citrullinemia toward a lifelong awareness of the disorder.
轻度瓜氨酸血症是经典I型瓜氨酸血症的一种等位基因变体，也是由尿素循环酶精氨琥珀酸合成酶（ASS）缺乏引起的。受影响的患者具有生化表型，但无临床表型。然而，没有可靠的参数能够推断该疾病的病程或其表现类型。本研究的目的是检验ASS残余活性水平的变化对诊断时严重程度的重要性。细菌体外表达研究允许对纯化的野生型和突变型ASS蛋白p.Ala118Thr（c.352G>A）、p.Trp179Arg（c.535T>C）、p.Val263Met（c.787G>A）、p.Arg265Cys（c.793C>T）、p.Met302Val（c.904A>G）、p.Gly324Ser（c.970G>A）、p.Gly362Val（c.1085G>T）和p.Gly390Arg（c.1168G>A）进行酶分析。在所选系统中，经典突变不显示任何显著的酶活性，而与轻度病程相关的突变产生显著的ASS活性水平。突变p.Ala118Thr（c.352G>A）具有较高的残余活性（62%），但对底物瓜氨酸和天冬氨酸的亲和力严重降低，令人印象深刻。该突变是在一名既往健康的成年女性中发现的，她没有已知瓜氨酸血症病史，在产后因高氨血症昏迷死亡。本研究结果表明，即使ASS残余活性水平较高，也不是临床病程平稳的可靠预后标志物。因此，测定ASS残余活性无助于预测代谢紊乱的风险。本研究应指导临床医生以及轻度瓜氨酸血症患者对该疾病保持终身警惕。
