Reduced Generation of Multiple Motile Cilia: A severe novel respiratory ciliopathy

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Multiple motile cilia line our airways and make an essential contribution to clearing the upper and lower respiratory tract to prevent infection and chronic inflammatory. We have been able to describe a novel motile ciliopathy within the group of mucociliary clearance disorders: Reduced Generation of Multiple Motile Cilia (RGMC). RGMC affected suffer from chronic destructive airway disease. Unfortunatelly RGMC is difficult to diagnose because secondary changes caused by inflammation can resemble the picture seen in respiratory epithelia of RGMC affected. In RGMC there is markedly reduced formation of cilia and/or ciliated cells due to autosomal recessive mutations in CCNO and MCIDAS. In the first funding period among other novel gene defects (e.g. NEK10) we identified recessive TP73 and autosomal dominant de novo mutations in FOXJ1 causing RGMC with lissencephaly and hydrocephalus, respectively. Our previous studies indicated that in CCNO and MCIDAS mutant respiratory epithelia the number of basal bodies and cilia is severely reduced. While the number of basal bodies was not severely altered in TP73 and FOXJ1 mutant cells the number of cilia was reduced. Our analyses in airliquid interface cultures of TP73 mutant respiratory epithelia revealed that not only the process of ciliogenesis is affected, but also cell proliferation and or differentiation of the respiratory epithelia is altered. This is of high clinical importance because changes in cell composition enable a new deeper understanding of the underlying disease mechanisms. Within this project we will therefore further i. characterize the process of human multiciliogenesis, cell differentiation and cell proliferation in new and already known RGMC defects ii. perform identification and characterization of further RGMC individuals as well as novel genes related to RGMC using next generation sequencing approaches iii. perform genotype-phenotype analysis in RGMC affected.