PMID- 35372502
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20220405
IS  - 2296-889X (Print)
IS  - 2296-889X (Electronic)
IS  - 2296-889X (Linking)
VI  - 9
DP  - 2022
TI  - SLC6A14 Impacts Cystic Fibrosis Lung Disease Severity via mTOR and Epithelial 
      Repair Modulation.
PG  - 850261
LID - 10.3389/fmolb.2022.850261 [doi]
LID - 850261
AB  - Cystic fibrosis (CF), due to pathogenic variants in CFTR gene, is associated with 
      chronic infection/inflammation responsible for airway epithelium alteration and 
      lung function decline. Modifier genes induce phenotype variability between people 
      with CF (pwCF) carrying the same CFTR variants. Among these, the gene encoding 
      for the amino acid transporter SLC6A14 has been associated with lung disease 
      severity and age of primary airway infection by the bacteria Pseudomonas 
      aeruginosa. In this study, we investigated whether the single nucleotide 
      polymorphism (SNP) rs3788766, located within SLC6A14 promoter, is associated with 
      lung disease severity in a large French cohort of pwCF. We also studied the 
      consequences of this SNP on SLC6A14 promoter activity using a luciferase reporter 
      and the role of SLC6A14 in the mechanistic target of rapamycin kinase (mTOR) 
      signaling pathway and airway epithelial repair. We confirm that SLC6A14 rs3788766 
      SNP is associated with lung disease severity in pwCF (p = 0.020; n = 3,257, 
      pancreatic insufficient, aged 6-40 years old), with the minor allele G being 
      deleterious. In bronchial epithelial cell lines deficient for CFTR, SLC6A14 
      promoter activity is reduced in the presence of the rs3788766 G allele. SLC6A14 
      inhibition with a specific pharmacological blocker reduced (3)H-arginine 
      transport, mTOR phosphorylation, and bronchial epithelial repair rates in wound 
      healing assays. To conclude, our study highlights that SLC6A14 genotype might 
      affect lung disease severity of people with cystic fibrosis via mTOR and 
      epithelial repair mechanism modulation in the lung.
CI  - Copyright (c) 2022 Mercier, Calmel, Mesinele, Sutanto, Merabtene, Longchampt, Sage, 
      Kicic, Boelle, Corvol, Ruffin and Guillot.
FAU - Mercier, Julia
AU  - Mercier J
AD  - Sorbonne Universite, Inserm, Centre de Recherche Saint Antoine, CRSA, Paris, 
      France.
FAU - Calmel, Claire
AU  - Calmel C
AD  - Sorbonne Universite, Inserm, Centre de Recherche Saint Antoine, CRSA, Paris, 
      France.
FAU - Mesinele, Julie
AU  - Mesinele J
AD  - Sorbonne Universite, Inserm, Centre de Recherche Saint Antoine, CRSA, Paris, 
      France.
AD  - Sorbonne Universite, Inserm, Institut Pierre Louis D'epidemiologie et de Sante 
      Publique, IPLESP, APHP, Hopital Saint-Antoine, Paris, France.
FAU - Sutanto, Erika
AU  - Sutanto E
AD  - Telethon Kids Institute, University of Western Australia, Nedlands, WA, 
      Australia.
AD  - School of Population Health, Curtin University, Bentley, WA, Australia.
FAU - Merabtene, Fatiha
AU  - Merabtene F
AD  - Sorbonne Universite, Inserm, Centre de Recherche Saint Antoine, CRSA, Paris, 
      France.
FAU - Longchampt, Elisabeth
AU  - Longchampt E
AD  - Service D'Anatomie Pathologique, Hopital Foch, Suresnes, France.
FAU - Sage, Edouard
AU  - Sage E
AD  - Department de Chirurgie Thoracique et Transplantation Pulmonaire, Hopital Foch, 
      Suresnes, France.
AD  - UMR 0892 UVSQ-INRAE, VIM, Universite Paris-Saclay, Jouy-en-Josas, France.
FAU - Kicic, Anthony
AU  - Kicic A
AD  - Telethon Kids Institute, University of Western Australia, Nedlands, WA, 
      Australia.
AD  - School of Population Health, Curtin University, Bentley, WA, Australia.
AD  - Centre for Cell Therapy and Regenerative Medicine, Medical School, The University 
      of Western Australia, Nedlands, WA, Australia.
AD  - Department of Respiratory and Sleep Medicine, Perth Children's Hospital, 
      Nedlands, WA, Australia.
FAU - Boelle, Pierre-Yves
AU  - Boelle PY
AD  - Sorbonne Universite, Inserm, Institut Pierre Louis D'epidemiologie et de Sante 
      Publique, IPLESP, APHP, Hopital Saint-Antoine, Paris, France.
FAU - Corvol, Harriet
AU  - Corvol H
AD  - Sorbonne Universite, Inserm, Centre de Recherche Saint Antoine, CRSA, Paris, 
      France.
AD  - AP-HP, Hopital Trousseau, Service de Pneumologie Pediatrique, Paris, France.
FAU - Ruffin, Manon
AU  - Ruffin M
AD  - Sorbonne Universite, Inserm, Centre de Recherche Saint Antoine, CRSA, Paris, 
      France.
FAU - Guillot, Loic
AU  - Guillot L
AD  - Sorbonne Universite, Inserm, Centre de Recherche Saint Antoine, CRSA, Paris, 
      France.
LA  - eng
PT  - Journal Article
DEP - 20220309
PL  - Switzerland
TA  - Front Mol Biosci
JT  - Frontiers in molecular biosciences
JID - 101653173
PMC - PMC8965518
OTO - NOTNLM
OT  - SLC6A14
OT  - amino acid transporter
OT  - bronchial epithelial cells
OT  - cystic fibrosis
OT  - lung function
OT  - modifier genes
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2022/04/05 06:00
MHDA- 2022/04/05 06:01
PMCR- 2022/01/01
CRDT- 2022/04/04 05:33
PHST- 2022/01/07 00:00 [received]
PHST- 2022/02/16 00:00 [accepted]
PHST- 2022/04/04 05:33 [entrez]
PHST- 2022/04/05 06:00 [pubmed]
PHST- 2022/04/05 06:01 [medline]
PHST- 2022/01/01 00:00 [pmc-release]
AID - 850261 [pii]
AID - 10.3389/fmolb.2022.850261 [doi]
PST - epublish
SO  - Front Mol Biosci. 2022 Mar 9;9:850261. doi: 10.3389/fmolb.2022.850261. 
      eCollection 2022.