Acute liver failure due to disorders of intracellular trafficking: NBAS deficiency

• Applicant: Privatdozent Dr. Dominic Lenz
• Subject Area: Gastroenterology ; Pediatric and Adolescent Medicine
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 518295121

Acute liver failure in childhood is a rare but life-threatening event. In recent years, previously unknown genetic causes have been identified. Among those, disorders of intracellular trafficking represent a new, steadily growing group. So far, the pathomechanism is poorly understood and there are no specific therapeutic approaches for this group of disease. This is a particular burden on affected families. This project should contribute to the pathomechanistic understanding of this group of diseases and ultimately identify therapeutic options. The research project focuses on NBAS deficiency as the most prominent representative of this disease group in which recurrent episodes of acute liver failure can occur in the context of febrile infections (MIM # 616483). The protein NBAS (Neuroblastoma amplified sequence) as part of the NRZ (NBAS, RINT1, ZW10) complex, together with the syntaxin-18 complex, mediates the fusion of retrograde migrating COPI vesicles with the endoplasmic reticulum (ER). Furthermore, the NRZ complex recruits membrane components for the formation of large COPII vesicles at the ER exit sites and thus plays a decisive role in the secretory pathway. Due to its crucial cellular function, the clinical phenotype involves other organ systems in affected individuals; this concerns especially the skeletal system and growth. The experiments are therefore carried out on patient fibroblasts, on hepatocytes differentiated from patient-specific induced pluripotent stem cells and on hepatocytes (HepG2) modified by CRIPSR / Cas9. The aim of our research project is to (1) characterize the disturbed intracellular transport in NBAS-deficient cells. In addition, the effect on the secretion performance of the cells as a whole and in relation to cell-specific proteins will be investigated. Furthermore, (2) the cellular stress response (ER stress, oxidative stress) and the activated effector cascades (ERAD, autophagy, apoptosis) are analyzed. In a last step, therapeutic approaches are tested to modify cellular stress responses and prevent cell death. Importantly, the expected findings are not only relevant for patients with NBAS deficiency, but allow conclusions to be drawn about the entire disease group of intracellular transport defects and can make specific treatment options to come into reach.

• DFG Programme: Research Grants
• Co-Investigators: Dr. Sabine Maria Jung-Klawitter, Ph.D.; Privatdozent Dr. Christian Staufner