Understanding the role of argininosuccinate lyase transcript variants in the clinical and biochemical variability of the urea cycle disorder argininosuccinic aciduria

Hu, Liyan; Pandey, Amit Vikram; Eggimann, Sandra; Rüfenacht, Véronique; Möslinger, Dorothea; Nuoffer, Jean-Marc; Häberle, Johannes (2013). Understanding the role of argininosuccinate lyase transcript variants in the clinical and biochemical variability of the urea cycle disorder argininosuccinic aciduria. Journal of biological chemistry, 288(48), pp. 34599-611. American Society for Biochemistry and Molecular Biology 10.1074/jbc.M113.503128

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Argininosuccinic aciduria (ASA) is an autosomal recessive urea cycle disorder caused by deficiency of argininosuccinate lyase (ASL) with a wide clinical spectrum from asymptomatic to severe hyperammonemic neonatal onset life-threatening courses. We investigated the role of ASL transcript variants in the clinical and biochemical variability of ASA. Recombinant proteins for ASL wild type, mutant p.E189G, and the frequently occurring transcript variants with exon 2 or 7 deletions were (co-)expressed in human embryonic kidney 293T cells. We found that exon 2-deleted ASL forms a stable truncated protein with no relevant activity but a dose-dependent dominant negative effect on enzymatic activity after co-expression with wild type or mutant ASL, whereas exon 7-deleted ASL is unstable but seems to have, nevertheless, a dominant negative effect on mutant ASL. These findings were supported by structural modeling predictions for ASL heterotetramer/homotetramer formation. Illustrating the physiological relevance, the predominant occurrence of exon 7-deleted ASL was found in two patients who were both heterozygous for the ASL mutant p.E189G. Our results suggest that ASL transcripts can contribute to the highly variable phenotype in ASA patients if expressed at high levels. Especially, the exon 2-deleted ASL variant may form a heterotetramer with wild type or mutant ASL, causing markedly reduced ASL activity.

Item Type:	Journal Article (Original Article)
Division/Institute:	04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Institute of Clinical Chemistry 04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Paediatric Medicine > Endocrinology/Metabolic Disorders
UniBE Contributor:	Pandey, Amit Vikram, Nuoffer, Jean-Marc
Subjects:	600 Technology > 610 Medicine & health
ISSN:	0021-9258
Publisher:	American Society for Biochemistry and Molecular Biology
Funders:	[4] Swiss National Science Foundation
Projects:	[102] Pathogenesis of disorders caused by human P450 oxidoreductase mutations Official URL
Language:	English
Submitter:	Amit Vikram Pandey
Date Deposited:	24 Feb 2014 08:32
Last Modified:	06 Jan 2023 17:12
Publisher DOI:	10.1074/jbc.M113.503128
PubMed ID:	24136197
Uncontrolled Keywords:	Argininosuccinate Lyase (ASL), Argininosuccinic Aciduria (ASA), Computer Modeling, Homomeric/Heterotetrameric Protein, Metabolic Diseases, Recombinant Protein Expression, Transcript Variants, Transfection, Urea Cycle
URI:	https://boris.unibe.ch/id/eprint/41740