期刊
HUMAN MUTATION
卷 29, 期 10, 页码 1222-1227出版社
WILEY
DOI: 10.1002/humu.20784
关键词
argininosuccinate synthetase; ASS; mild citrullinemia; bacterial expression study; urea cycle
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.Va1263Met (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. Hum Mutat 29(10), 1222-1227, 2008. (c) 2008 Wiley-Liss, Inc.
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