Novel in vitro model of urea cycle disorder using citrullinemia type I patient-derived iPSCs

Citrullinemia type I is a genetic disorder determined by the genetic deficiency of argininosuccinate synthetase 1 (ASS1) gene, which leads to an accumulation of citrulline and ammonia. The outcome of the disease is fatal liver dysfunction and hepatic encephalopathy in the first days of life. Alternative pathway medications and protein restriction are attempted, but some cases are not controllable, needing liver transplantation. Induced pluripotent stem cells (iPSCs), a new technique to generate stem cells from differentiated cells, shed new light towards the understanding of several disease mechanisms and for new therapeutic approaches. We made iPSCs from peripheral blood cells taken from a citrullinemia type I patient to establish a disease model. We found that differentiated hepatocyte-like cells from the citrullinemia patient's iPSCs present hepatocyte characteristics with lower ammonia metabolization capacity and decreased urea production compared to those from healthy-donor iPSCs. These results indicate that citrullinemia-specific iPSCs can be a potential tool to discover new drugs for the treatment of citrullinemia and other urea cycle disorders.