Defining childhood interstitial lung disease on the molecular level: Insights into known and novel genetic entities predisposing to fibrosis

Schuch, Luise Antje (2022): Defining childhood interstitial lung disease on the molecular level: Insights into known and novel genetic entities predisposing to fibrosis. Dissertation, LMU München: Faculty of Biology

Abstract

Childhood interstitial lung diseases (chILD) are a heterogenous group of rare disorders affecting the pulmonary connective tissue scaffold and its associated structures. A subset of chILD cases develops pulmonary fibrosis (PF), a severe pathological lung remodeling process that is potentially life-threatening. Early identification of cases at high risk for developing PF is therefore crucial but remains a challenge in current clinical practice. As rare diseases are often hereditary monogenic traits, we used extended genetic analysis to study the molecular nature of chILD with PF features in children and adolescents. We provide an in-depth clinical characterization of a previously known but underexplored genetic disorder with PF, Hermansky-Pudlak syndrome type 2. In addition, novel genetic entities are presented that are linked to unique multisystem disorders associated with childhood PF. We relate bi-allelic variants in cytosolic phenylalanyl-tRNA synthetase genes (FARSA, FARSB) to a spectrum of multiorgan dysfunctions and continue to functionally analyze the role of the affected enzyme, FARS1, in aminoacylation and protein biosynthesis. We further identify a novel inborn error of immunity based on deficiency in ZNFX1, a viral nucleic acid sensor, and investigate its effects on immune regulation, viral clearance, and chronic inflammation. Lastly, this work offers perspectives on personalized treatment of chILD as a potential future therapy on the horizon.

• Item Type: Theses (Dissertation, LMU Munich)
• Subjects: 500 Natural sciences and mathematics; 500 Natural sciences and mathematics > 570 Life sciences
• Faculties: Faculty of Biology
• Language: English
• Date of oral examination: 14. July 2022
• 1. Referee: Osman, Christof
• Signature of the printed copy: 0001/UMC 28991