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

多个活动纤毛排列在我们的呼吸道上，对清除上呼吸道和下呼吸道以防止感染和慢性炎症做出重要贡献。我们已经能够描述一种新的运动性纤毛病变组内的粘液纤毛清除障碍：减少生成的多个运动纤毛（RGMC）。受影响的RGMC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类似于受影响的RGMC呼吸道上皮中所见的图像。在RGMC中，由于CCNO和MCIDAS中的常染色体隐性突变，纤毛和/或纤毛细胞的形成显著减少。在第一个资助期内，在其他新的基因缺陷（如NEK 10）中，我们确定了FOXJ 1中的隐性TP 73和常染色体显性从头突变，分别导致RGMC无脑畸形和脑积水。我们以前的研究表明，在CCNO和MCIDAS突变呼吸道上皮细胞的基体和纤毛的数量严重减少。虽然在TP 73和FOXJ 1突变细胞中基底体的数量没有严重改变，但纤毛的数量减少。我们在TP 73突变体呼吸道上皮细胞的气液界面培养中的分析显示，不仅纤毛发生的过程受到影响，而且呼吸道上皮细胞的细胞增殖和/或分化也被改变。这具有很高的临床重要性，因为细胞组成的变化使人们能够更深入地了解潜在的疾病机制。因此，在这个项目中，我们将进一步。表征新的和已知的RGMC缺陷中的人多纤毛发生、细胞分化和细胞增殖的过程使用下一代测序方法对其他RGMC个体以及与RGMC相关的新基因进行鉴定和表征iii.在受累RGMC中进行基因型-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.