The hsa-miR-125a/hsa-let-7e/hsa-miR-99b cluster is potentially implicated in Cystic Fibrosis pathogenesis

Cystic Fibrosis (CF) is an autosomal recessive disorder implicating the Cystic Fibrosis Transmembrane Regulator (CFTR). Even though CF is mainly considered an inherited monogenic disease, numerous findings over the last few years argue for a more complicated multifactorial disease involving modifier genes. The 19q13.2-19q13.4 region is suspected to contain genetic modifiers that correlate to the severity of CF.

Here we studied a cohort of p.F508del patients for potential SNPs in the hsa-miR-99b/hsa-let-7e/hsa-miR-125a cluster, which is found within the 19q13.2-19q13.4 region.

Three polymorphisms were identified in the hsa-miR-99b/hsa-let-7e/hsa-miR-125a cluster. Using a cell based model, we analysed whether expression of DeltaF508-CFTR influences the expression of mature hsa-miR-99b, hsa-let-7e, and hsa-miR-125a. We found that hsa-miR-99b and hsa-miR-125a were significantly increased in DeltaF508-CFTR expressing cells. The three miRNAs appear to be derived from the same precursor but differ in their expression levels suggesting differential maturation of these miRNAs in CF. In silico analysis revealed that two out of the three polymorphisms we identified in a CF p.F508del patients cohort could modulate miRNA maturation and therefore impact on hsa-miR-99b/hsa-let-7e/hsa-miR-125a expression levels.

Ingenuity Pathway Analysis indicated that hsa-miR-99b and hsa-miR-125a could be associated with the phenotypes manifested by p.F508del patients. Here we provide novel elements in the mechanism of hsa-miR-99b and hsa-miR-125a biogenesis, and for the role of CFTR and DeltaF508-CFTR on the expression of this miRNA cluster. These findings augment existing data implicating miRNAs as putative CF modifiers.