Cilia are antenna like projections extending from the cell surface. Two main types can be distinguished: motile cilia essential for movement of fluids and non-motile cilia crucial for cell signalling pathways, enabling proper embryonic development and maintaining organ function. Motile cilia dysfunction can cause left-right body axis defects, heart defects as well as recurrent respirator infections and reduced fertility in humans. malfunction of non-motile cilia often results in complex developmental defects affecting the kidneys, eyes, brain, heart, liver and the skeleton. Over 100 genes have been found to be defective in ciliopathies, however a large number of cases is still genetically unexplained. As many as 1 in 1000 persons in Europe is affected by a cilia related genetic diseases, imposing huge health and socioeconomic challenges. There is currently no causative treatment option available.
TREATCilia aimed to uncover underlying molecular pathophysiology in dynein based ciliopathies from gene to mechanism and we hope to identify future pharmacological entry points to ameliorate ciliary dynein-related phenotypes. Emplyoing exome sequencing, we were able to identify several novel human disease genes, such as PIH1D3, MNS1 and DNAH9, causing cilia motility defects and/or laterality defects when mutated as well as several novel genes associated with centra nervous system defects. In addition, we were able to establish a number of phenotype genotype correlation for motile ciliopathies/laterality disorders, inherited renal and skeletal phenotypes and neuro-developmental disorders By creating several of dynein-2- and IFT-mutant cell lines harboring human disease alleles using CRISPR base editing technologies, the project achieved generation of unique in-vitro ciliary condrodysplasia disease models. Multi-omics analyses of these model suggest disturbed Golgi-transport, actin-cytoskeleton modifications and changed extracellular matrix composition in mutants. We further identified a number of affected cell signalling pathways, offering putative future therapeutic targets.
