Unstable argininosuccinate lyase in variant forms of the urea cycle disorder argininosuccinic aciduria

Journal of Inherited Metabolic Disease
Liyan HuJohannes Häberle

Abstract

Loss of function of the urea cycle enzyme argininosuccinate lyase (ASL) is caused by mutations in the ASL gene leading to ASL deficiency (ASLD). ASLD has a broad clinical spectrum ranging from life-threatening severe neonatal to asymptomatic forms. Different levels of residual ASL activity probably contribute to the phenotypic variability but reliable expression systems allowing clinically useful conclusions are not yet available. In order to define the molecular characteristics underlying the phenotypic variability, we investigated all ASL mutations that were hitherto identified in patients with late onset or mild clinical and biochemical courses by ASL expression in human embryonic kidney 293 T cells. We found residual activities >3% of ASL wild type (WT) in nine of 11 ASL mutations. Six ASL mutations (p.Arg95Cys, p.Ile100Thr, p.Val178Met, p.Glu189Gly, p.Val335Leu, and p.Arg379Cys) with residual activities ≥16% of ASL WT showed no significant or less than twofold reduced Km values, but displayed thermal instability. Computational structural analysis supported the biochemical findings by revealing multiple effects including protein instability, disruption of ionic interactions and hydrogen bonds between residues in the monomer...Continue Reading

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Citations

Jan 10, 2016·Molecular Diagnosis & Therapy·Corinne InauenJohannes Häberle
Feb 7, 2019·Journal of Inherited Metabolic Disease·Julien BaruteauJohannes Häberle
May 16, 2020·Molecular Genetics & Genomic Medicine·Zhenzhu ZhengQingliu Fu
Apr 16, 2019·Journal of Inherited Metabolic Disease·Johannes HäberleCarlo Dionisi-Vici
Mar 3, 2017·Journal of Inherited Metabolic Disease·Julien BaruteauJames E Davison
Feb 22, 2021·Journal of Cellular and Molecular Medicine·Fang LiuShao-Guang Lv

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