title: Modelling urea-cycle disorder citrullinemia type 1 with disease-specific iPSCs.
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.
authors.affiliation: 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.
authors.forename: Elena Yukie
authors.initials: EY
authors.lastname: Yoshitoshi-Uebayashi
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan.
authors.forename: Taro
authors.initials: T
authors.lastname: Toyoda
authors.affiliation: 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.
authors.forename: Katsutaro
authors.initials: K
authors.lastname: Yasuda
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Kotaka
authors.affiliation: Department of Pediatrics, Kitasato University School of Medicine, Kanagawa, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Nomoto
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Okita
authors.affiliation: Department of Hepatobiliary, Pancreatic, Transplantation and Pediatric Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Yasuchika
authors.affiliation: Department of Hepatobiliary, Pancreatic, Transplantation and Pediatric Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Okamoto
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Juntendo University, Tokyo, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Takubo
authors.affiliation: Department of Pediatrics, Center for Perinatal Medicine, Nara Medical University, Nara, Japan.
authors.forename: Toshiya
authors.initials: T
authors.lastname: Nishikubo
authors.affiliation: Institute for Advanced Biosciences, Keio University, Yamagata, Japan.
authors.forename: Tomoyoshi
authors.initials: T
authors.lastname: Soga
authors.affiliation: Department of Hepatobiliary, Pancreatic, Transplantation and Pediatric Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Uemoto
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan. Electronic address: osafu@cira.kyoto-u.ac.jp.
authors.forename: Kenji
authors.initials: K
authors.lastname: Osafune
mesh_terms: D000818:Animals; D001120:Arginine / Q000494:pharmacology*; D001124:Argininosuccinate Synthase / Q000172:deficiency* / Q000235:genetics; D001483:Base Sequence; D002454:Cell Differentiation; D002952:Citric Acid Cycle / Q000187:drug effects* / Q000235:genetics; D020159:Citrullinemia / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007621:Karyotyping; D055442:Metabolome; D051379:Mice; D016688:Mice, Inbred NOD; D008954:Models, Biological; D061251:Primary Cell Culture; D015398:Signal Transduction; D014508:Urea / Q000378:metabolism
chemical_list: D014508:Urea; D001120:Arginine; D001124:Argininosuccinate Synthase
keywords: Argininosuccinate synthetase; Citrullinemia type 1; Hepatocyte; Urea cycle disorder; iPSC; l-arginine