Deciphering biallelic CIAO3 variants as a novel monogenic cause of pulmonary capillary haemangiomatosis

• Applicant: Florian Gothe, Ph.D.
• Subject Area: Pediatric and Adolescent Medicine
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 563110396

The aim of this project is to study the role of CIAO3 in human disease thereby defining CIAO3 deficiency as the cause of a new monogenic lung disease. Beyond clarifying disease origins in a very limited number of affected individuals, we hope to characterize another essential and potentially druggable pathway relevant to human pulmonary hypertension development. To do so, we wish to test the following hypotheses: Does reduced CIAO3 function disrupt angiogenesis? Since all patients show abnormal proliferation of capillaries within the alveolar septae, we are expecting CIAO3 malfunction to cause endothelial dysfunction. To this end, iPSCs clones carrying the CIAO3 c.307-5T>G variant in homozygous fashion will be differentiated into Blood Vessel Organoids (BVO). We will study the capacity of the mutant cells to differentiate into BVOs, their strategies to cope with reactive oxygen species and the involvement of various kown proangiogenic pathways, e.g. HIF1alpha pathway. Is the high oxygen tension in pulmonary capillaries responsible for the observed organ specificity? It is somewhat surprising that a defect in cytosolic Fe/S cluster biogenesis, which is relevant to basically all cell types in eukaryotes, causes an exclusively pulmonary vessel phenotype. One unique feature of pulmonary capillaries is their exposure to high oxygen tension. We will therefore differentiate cells under different oxygen concentrations to see whether potential defects might be ameliorated by hypoxia. Is Fe/S cluster binding compromised in the CIAO3 p.G192S protein? The mechanism underlying defective function is unkown in one of the six variants under study. The c.574G>A variant is close to the C-terminal Fe/S-cluster binding site of CIAO3 and thus impaired cluster-binding capacity is expected. To address this question, Fe-incorporation into the CIAO3 p.G192S protein will be assessed.

• DFG Programme: Research Grants