Geremek Maciej, Ziętkiewicz Ewa, Bruinenberg Marcel, Franke Lude, Pogorzelski Andrzej, Wijmenga Cisca, Witt Michał
International Institute of Molecular and Cell Biology, Warsaw, Poland ; Genetics Department, University Medical Centre Groningen and University of Groningen, Groningen, the Netherlands ; Complex Genetics Group, Department of Biomedical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.
Department of Molecular and Clinical Genetics, Institute of Human Genetics, Poznan, Poland.
PLoS One. 2014 Feb 6;9(2):e88216. doi: 10.1371/journal.pone.0088216. eCollection 2014.
Primary ciliary dyskinesia (PCD) is a rare, genetically heterogeneous disease characterized by recurrent respiratory tract infections, sinusitis, bronchiectasis and male infertility. The pulmonary phenotype in PCD is caused by the impaired motility of cilia in the respiratory epithelium, due to ultrastructural defects of these organelles. We hypothesized that defects of multi-protein ciliary complexes should be reflected by gene expression changes in the respiratory epithelium. We have previously found that large group of genes functionally related to cilia share highly correlated expression pattern in PCD bronchial tissue. Here we performed an explorative analysis of differential gene expression in the bronchial tissue from six PCD patients and nine non-PCD controls, using Illumina HumanRef-12 Whole Genome BeadChips. We observed 1323 genes with at least 2-fold difference in the mean expression level between the two groups (t-test p-value <0.05). Annotation analysis showed that the genes down-regulated in PCD biopsies (602) were significantly enriched for terms related to cilia, whereas the up-regulated genes (721) were significantly enriched for terms related to cell cycle and mitosis. We assembled a list of human genes predicted to encode ciliary proteins, components of outer dynein arms, inner dynein arms, radial spokes, and intraflagellar transport proteins. A significant down-regulation of the expression of genes from all the four groups was observed in PCD, compared to non-PCD biopsies. Our data suggest that a coordinated down-regulation of the ciliome genes plays an important role in the molecular pathomechanism of PCD.
原发性纤毛运动障碍（PCD）是一种罕见的、基因异质性疾病，其特征为反复呼吸道感染、鼻窦炎、支气管扩张和男性不育。PCD的肺部表型是由呼吸道上皮细胞纤毛运动受损所致，这是由于这些细胞器的超微结构缺陷。我们推测多蛋白纤毛复合体的缺陷应通过呼吸道上皮细胞的基因表达变化得以体现。我们之前发现，一大组与纤毛功能相关的基因在PCD支气管组织中具有高度相关的表达模式。在此，我们使用Illumina HumanRef-12全基因组芯片，对6例PCD患者和9例非PCD对照的支气管组织中的差异基因表达进行了探索性分析。我们观察到两组之间平均表达水平至少有2倍差异的基因有1323个（t检验p值<0.05）。注释分析表明，PCD活检组织中下调的基因（602个）显著富集于与纤毛相关的术语，而上调的基因（721个）则显著富集于与细胞周期和有丝分裂相关的术语。我们整理了一份预计编码纤毛蛋白、外动力臂组件、内动力臂组件、辐条和鞭毛内运输蛋白的人类基因列表。与非PCD活检组织相比，PCD中所有四组基因的表达均显著下调。我们的数据表明，纤毛组基因的协同下调在PCD的分子发病机制中起重要作用。
