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ASS1 deficiency is associated with impaired neuronal differentiation in zebrafish larvae

Citrullinemia type 1 (CTLN1) is a rare autosomal recessive urea cycle disorder caused by deficiency of the cytosolic enzyme argininosuccinate synthetase 1 (ASS1) due to pathogenic variants in the ASS1 gene located on chromosome 9q34.11. Even though hyperammenomia is considered the major pathomechani...

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Main Authors: Seidl, Marie (Author) , Scharré, Svenja (Author) , Posset, Roland (Author) , Druck, Ann-Catrin (Author) , Epp, Friederike (Author) , Okun, Jürgen G. (Author) , Dimitrov, Bianca (Author) , Hoffmann, Georg F. (Author) , Kölker, Stefan (Author) , Zielonka, Matthias (Author)
Format: Article (Journal)
Language:English
Published: January 2024
In: Molecular genetics and metabolism
Year: 2024, Volume: 141, Issue: 1, Pages: 1-11
ISSN:1096-7206
DOI:10.1016/j.ymgme.2023.108097
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1016/j.ymgme.2023.108097
Verlag, kostenfrei, Volltext: https://www.sciencedirect.com/science/article/pii/S1096719223007278
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Author Notes:Marie J. Seidl, Svenja Scharre, Roland Posset, Ann-Catrin Druck, Friederike Epp, Jürgen G. Okun, Bianca Dimitrov, Georg F. Hoffmann, Stefan Kölker, Matthias Zielonka
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Summary:Citrullinemia type 1 (CTLN1) is a rare autosomal recessive urea cycle disorder caused by deficiency of the cytosolic enzyme argininosuccinate synthetase 1 (ASS1) due to pathogenic variants in the ASS1 gene located on chromosome 9q34.11. Even though hyperammenomia is considered the major pathomechanistic factor for neurological impairment and cognitive dysfunction, a relevant subset of individuals presents with a neurodegenerative course in the absence of hyperammonemic decompensations. Here we show, that ASS1 deficiency induced by antisense-mediated knockdown of the zebrafish ASS1 homologue is associated with defective neuronal differentiation ultimately causing neuronal cell loss and consecutively decreased brain size in zebrafish larvae in vivo. Whereas ASS1-deficient zebrafish larvae are characterized by markedly elevated concentrations of citrulline - the biochemical hallmark of CTLN1, accumulation of L-citrulline, hyperammonemia or therewith associated secondary metabolic alterations did not account for the observed phenotype. Intriguingly, coinjection of the human ASS1 mRNA not only normalized citrulline concentration but also reversed the morphological cerebral phenotype and restored brain size, confirming conserved functional properties of ASS1 across species. The results of the present study imply a novel, potentially non-enzymatic (moonlighting) function of the ASS1 protein in neurodevelopment.
Item Description:Online verfügbar: 28. November 2023, Artikelversion: 18. Dezember 2023
Gesehen am 06.03.2024
Physical Description:Online Resource
ISSN:1096-7206
DOI:10.1016/j.ymgme.2023.108097

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