Cystic Fibrosis: Systems Biology Analysis from Homozygous p.Phe508del Variant Patients’ Samples Reveals Perturbations in Tissue-Specific Pathways

Abstract

Cystic fibrosis (CF) is an autosomal recessive disorder, caused by diverse genetic variants for the CF transmembrane conductance regulator (CFTR) protein. Among these, p.Phe508del is the most prevalent variant. The effects of this variant on the physiology of each tissue remains unknown. This study is aimed at predicting cell signaling pathways present in different tissues of fibrocystic patients, homozygous for p.Phe508del. The study involved analysis of two microarray datasets, E-GEOD-15568 and E-MTAB-360 corresponding to the rectal and bronchial epithelium, respectively, obtained from the ArrayExpress repository. Particularly, differentially expressed genes (DEGs) were predicted, protein-protein interaction (PPI) networks were designed, and centrality and functional interaction networks were analyzed. The study reported that p.Phe508del-mutated CFTR-allele in homozygous state influenced the whole gene expression in each tissue differently. Interestingly, gene ontology (GO) term enrichment analysis revealed that only “neutrophil activation” was shared between both tissues; however, nonshared DEGs were grouped into the same GO term. For further verification, functional interaction networks were generated, wherein no shared nodes were reported between these tissues. These results suggested that the p.Phe508del-mutated CFTR-allele in homozygous state promoted tissue-specific pathways in fibrocystic patients. The generated data might further assist in prediction diagnosis to define biomarkers or devising therapeutic strategies.

In Utero Mapping and Development Role of CFTR in Lung and Gastrointestinal Tract of Cystic Fibrosis Patients

“…This work highlights that using the high-throughput screening variant of mammalian membrane two-hybrid technology can discover novel interactions of biological importance for CFTR. Poloni et al used two microarray data sets, E-GEOD-15568 and E-MTAB-360, to investigate differentially expressed genes in F508del-CFTR patients, albeit only for rectal and bronchial epithelium, respectively . The authors found that F508del-CFTR influenced the gene expression of each tissue differently; only “neutrophil activation” was shared between the tissues investigated.…”

“…Poloni et al used two microarray data sets, E-GEOD-15568 and E-MTAB-360, to investigate differentially expressed genes in F508del-CFTR patients, albeit only for rectal and bronchial epithelium, respectively. 41 The authors found that F508del-CFTR influenced the gene expression of each tissue differently; only "neutrophil activation" was shared between the tissues investigated. This suggests a comprehensive insight into the molecular networks of CF epithelia (albeit limited to bronchial and rectal epithelia) and the underlying regulators involved in CF.…”