| Abstract |
RAD50-interacting protein1 (RINT1) deficiency has been implicated in recurrent acute liver failure (RALF) triggered by fever or infections. RINT1, together with neuroblastoma amplified sequence and Zeste White 10 (forming the NRZ complex), localizes at the interface between the endoplasmic reticulum and Golgi apparatus, where it plays a key role in vesicular trafficking. However, the mechanisms by which RINT1 deficiency leads to RALF remain unclear. This study aimed to describe a woman with RALF harboring a homozygous missense mutation in RINT1. Induced pluripotent stem cells (iPSCs) were generated from the patient's mononuclear cells and differentiated into hepatocyte-like cells (HLCs). Upon exposure to high temperature (40°C), RINT1-deficient HLCs exhibited cellular damage characteristic of RALF. Furthermore, these cells also demonstrated heightened sensitivity to cytokines and viral mimetics while showing comparatively lower responsiveness to bacterial infection-related stimuli. Transcriptome sequencing revealed dysregulated gene expression associated with the extracellular matrix (ECM). Additionally, glycosaminoglycan disaccharide analysis revealed abnormal levels of chondroitin sulfate, heparan sulfate, and hyaluronan in RINT1-deficient HLCs. In conclusion, HLCs derived from RINT1-deficient iPSCs serve as a valuable model for investigating RINT1-related liver pathogenesis. The results suggest that cytokine responses, particularly those triggered by viral infections, play a central role in the development of RALF. Furthermore, ECM alterations provided novel insights into the potential role of RINT1 defects in RALF.
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