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 journalArticle

4 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

Fingerprint

Citrullinemia
Inborn Urea Cycle Disorder
Induced Pluripotent Stem Cells
Stem cells
Urea
Argininosuccinate Synthase
Metabolites
Arginine
Genes
Citric Acid Cycle
Amino Acids
Enzymes
Hepatocytes
Hyperammonemia
Phenotype
Metabolome
Therapeutics
Newborn Infant
Mutation

Keywords

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

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Yoshitoshi-Uebayashi, E. Y., Toyoda, T., Yasuda, K., Kotaka, M., Nomoto, K., Okita, K., ... Osafune, K. (2017). Modelling urea-cycle disorder citrullinemia type 1 with disease-specific iPSCs. Biochemical and Biophysical Research Communications, 486(3), 613-619. https://doi.org/10.1016/j.bbrc.2017.03.037

Modelling urea-cycle disorder citrullinemia type 1 with disease-specific iPSCs. / Yoshitoshi-Uebayashi, Elena Yukie; Toyoda, Taro; Yasuda, Katsutaro; Kotaka, Maki; Nomoto, Keiko; Okita, Keisuke; Yasuchika, Kentaro; Okamoto, Shinya; Takubo, Noriyuki; Nishikubo, Toshiya; Soga, Tomoyoshi; Uemoto, Shinji; Osafune, Kenji.

In: Biochemical and Biophysical Research Communications, Vol. 486, No. 3, 06.05.2017, p. 613-619.

Research output: Contribution to journalArticle

Yoshitoshi-Uebayashi, EY, Toyoda, T, Yasuda, K, Kotaka, M, Nomoto, K, Okita, K, Yasuchika, K, Okamoto, S, Takubo, N, Nishikubo, T, Soga, T, Uemoto, S & Osafune, K 2017, 'Modelling urea-cycle disorder citrullinemia type 1 with disease-specific iPSCs', Biochemical and Biophysical Research Communications, vol. 486, no. 3, pp. 613-619. https://doi.org/10.1016/j.bbrc.2017.03.037
Yoshitoshi-Uebayashi, Elena Yukie ; Toyoda, Taro ; Yasuda, Katsutaro ; Kotaka, Maki ; Nomoto, Keiko ; Okita, Keisuke ; Yasuchika, Kentaro ; Okamoto, Shinya ; Takubo, Noriyuki ; Nishikubo, Toshiya ; Soga, Tomoyoshi ; Uemoto, Shinji ; Osafune, Kenji. / Modelling urea-cycle disorder citrullinemia type 1 with disease-specific iPSCs. In: Biochemical and Biophysical Research Communications. 2017 ; Vol. 486, No. 3. pp. 613-619.
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