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

多条活动的纤毛排列在我们的气道上，对清理上呼吸道和下呼吸道做出重要贡献，以防止感染和慢性炎症。我们已经能够在粘液纤毛清除障碍组中描述一种新的运动性纤毛病：减少多发运动性纤毛（RGMC）的产生。RGMC患者患有慢性破坏性气道疾病。不幸的是，RGMC很难诊断，因为炎症引起的继发性变化与RGMC感染的呼吸道上皮类似。在RGMC中，由于CCNO和MCIDAS的常染色体隐性突变，纤毛和/或纤毛细胞的形成明显减少。在第一个资助期，在其他新的基因缺陷（如NEK10）中，我们发现FOXJ1的隐性TP73和常染色体显性新生突变分别导致RGMC无脑畸形和脑积水。我们之前的研究表明，在CCNO和MCIDAS突变的呼吸上皮中，基底体和纤毛的数量严重减少。TP73和FOXJ1突变体细胞的基底体数量变化不大，但纤毛数量减少。我们对TP73突变呼吸上皮的气液界面培养分析表明，不仅纤毛发生过程受到影响，而且呼吸上皮细胞的增殖和分化也发生了改变。这具有很高的临床重要性，因为细胞组成的变化使人们对潜在的疾病机制有了新的更深入的了解。因此，在这个项目中，我们将进一步1 .描述新的和已知的RGMC缺陷中人类多毛发生、细胞分化和细胞增殖的过程2。使用下一代测序方法对进一步的RGMC个体以及与RGMC相关的新基因进行鉴定和表征。对RGMC患者进行基因型-表型分析。

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.