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Biochem Biophys Res Commun. 2017 May 6;486(3):613-619. doi: 10.1016/j.bbrc.2017.03.037. Epub 2017 Mar 14.

Modelling urea-cycle disorder citrullinemia type 1 with disease-specific iPSCs.

Author information

1
Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan; Department of Hepatobiliary, Pancreatic, Transplantation and Pediatric Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
2
Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan.
3
Department of Pediatrics, Kitasato University School of Medicine, Kanagawa, Japan.
4
Department of Hepatobiliary, Pancreatic, Transplantation and Pediatric Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
5
Department of Pediatrics and Adolescent Medicine, Juntendo University, Tokyo, Japan.
6
Department of Pediatrics, Center for Perinatal Medicine, Nara Medical University, Nara, Japan.
7
Institute for Advanced Biosciences, Keio University, Yamagata, Japan.
8
Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan. Electronic address: osafu@cira.kyoto-u.ac.jp.

Abstract

Citrullinemia type 1 (CTLN1) is a urea cycle disorder (UCD) caused by mutations of the ASS1 gene, which is responsible for production of the enzyme argininosuccinate synthetase (ASS), and classically presented as life-threatening hyperammonemia in newborns. Therapeutic options are limited, and neurological sequelae may persist. To understand the pathophysiology and find novel treatments, induced pluripotent stem cells (iPSCs) were generated from a CTLN1 patient and differentiated into hepatocyte-like cells (HLCs). CTLN1-HLCs have lower ureagenesis, recapitulating part of the patient's phenotype. l-arginine, an amino acid clinically used for UCD treatment, improved this phenotype in vitro. Metabolome analysis revealed an increase in tricarboxylic acid (TCA) cycle metabolites in CTLN1, suggesting a connection between CTLN1 and the TCA cycle. This CTLN1-iPSC model improves the understanding of CTLN1 pathophysiology and can be used to pursue new therapeutic approaches.

KEYWORDS:

Argininosuccinate synthetase; Citrullinemia type 1; Hepatocyte; Urea cycle disorder; iPSC; l-arginine

PMID:
28302489
DOI:
10.1016/j.bbrc.2017.03.037
[Indexed for MEDLINE]

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