title: The hsa-miR-125a/hsa-let-7e/hsa-miR-99b cluster is potentially implicated in Cystic Fibrosis pathogenesis.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: INRA, UMR 1313 Génétique Animale et Biologie Intégrative, Domaine de Vilvert, F-78350 Jouy-en-Josas, France.
authors: Marie-Laure
authors: ML
authors: Endale Ahanda
authors: Inserm U567 - CNRS UMR 8104 - IFR 116 Institut Cochin 22, rue Méchain, 75014 Paris, France.
authors: Thierry
authors: T
authors: Bienvenu
authors: Inserm U845, Université Descartes Paris 5, 156 rue de Vaugirard, 75730 Paris Cedex 15, France.
authors: Isabelle
authors: I
authors: Sermet-Gaudelus
authors: CNRS, UMR 5088, LBCMCP, Université de Toulouse, 118 route de Narbonne, 31062 Toulouse Cedex 09, France.
authors: Laurent
authors: L
authors: Mazzolini
authors: Inserm U845, Université Descartes Paris 5, 156 rue de Vaugirard, 75730 Paris Cedex 15, France.
authors: Aleksander
authors: A
authors: Edelman
authors: Inserm, UMR-S945, Institut Fédératif de Recherches (IFR) 113, Immunité-Cancer-Infection-Hôpital Pitié-Salpêtrière, 83 Bld de l'Hôpital, 75651 Paris Cedex 13, France.
authors: Rima
authors: R
authors: Zoorob
authors: CNRS, UMR 5547, Université de Toulouse, 118 route de Narbonne, 31062 Toulouse Cedex 09, France.
authors: Noélie
authors: N
authors: Davezac
mesh_terms: D002460:Cell Line; D003550:Cystic Fibrosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000096:biosynthesis / Q000235:genetics*; D004247:DNA / Q000235:genetics*; D005500:Follow-Up Studies; D005786:Gene Expression Regulation; D006801:Humans; D015151:Immunoblotting; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: C531888:MIRN125 microRNA, human; D035683:MicroRNAs; C093349:cystic fibrosis transmembrane conductance regulator delta F508; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D004247:DNA
keywords: CFTR; Cystic Fibrosis; MicroRNAs; SNPs