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

Elena Yukie Yoshitoshi-Uebayashi, Taro Toyoda, Katsutaro Yasuda, Maki Kotaka, Keiko Nomoto, Keisuke Okita, Kentaro Yasuchika, Shinya Okamoto, Noriyuki Takubo, Toshiya Nishikubo, Tomoyoshi Soga, Shinji Uemoto, Kenji Osafune

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)613-619
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume486
Issue number3
DOIs
Publication statusPublished - 2017 May 6

Keywords

  • Argininosuccinate synthetase
  • Citrullinemia type 1
  • Hepatocyte
  • L-arginine
  • Urea cycle disorder
  • iPSC

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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