PMID- 37325471
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20230619
IS  - 2296-889X (Print)
IS  - 2296-889X (Electronic)
IS  - 2296-889X (Linking)
VI  - 10
DP  - 2023
TI  - Q1291H-CFTR molecular dynamics simulations and ex vivo theratyping in nasal 
      epithelial models and clinical response to elexacaftor/tezacaftor/ivacaftor in a 
      Q1291H/F508del patient.
PG  - 1148501
LID - 10.3389/fmolb.2023.1148501 [doi]
LID - 1148501
AB  - Background: Cystic fibrosis (CF) is caused by a wide spectrum of mutations in the 
      CF transmembrane conductance regulator (CFTR) gene, with some leading to 
      non-classical clinical presentations. We present an integrated in vivo, in silico 
      and in vitro investigation of an individual with CF carrying the rare Q1291H-CFTR 
      allele and the common F508del allele. At age 56 years, the participant had 
      obstructive lung disease and bronchiectasis, qualifying for 
      Elexacaftor/Tezacaftor/Ivacaftor (ETI) CFTR modulator treatment due to their 
      F508del allele. Q1291H CFTR incurs a splicing defect, producing both a normally 
      spliced but mutant mRNA isoform and a misspliced isoform with a premature 
      termination codon, causing nonsense mediated decay. The effectiveness of ETI in 
      restoring Q1291H-CFTR is largely unknown. Methods: We collected clinical endpoint 
      measurements, including forced expiratory volume in 1 s percent predicted 
      (FEV1pp) and body mass index (BMI), and examined medical history. In silico 
      simulations of the Q1291H-CFTR were compared to Q1291R, G551D, and wild-type 
      (WT)-CFTR. We quantified relative Q1291H CFTR mRNA isoform abundance in 
      patient-derived nasal epithelial cells. Differentiated pseudostratified airway 
      epithelial cell models at air liquid interface were created and ETI treatment 
      impact on CFTR was assessed by electrophysiology assays and Western blot. 
      Results: The participant ceased ETI treatment after 3 months due to adverse 
      events and no improvement in FEV1pp or BMI. In silico simulations of Q1291H-CFTR 
      identified impairment of ATP binding similar to known gating mutants Q1291R and 
      G551D-CFTR. Q1291H and F508del mRNA transcripts composed 32.91% and 67.09% of 
      total mRNA respectively, indicating 50.94% of Q1291H mRNA was misspliced and 
      degraded. Mature Q1291H-CFTR protein expression was reduced (3.18% +/- 0.60% of 
      WT/WT) and remained unchanged with ETI. Baseline CFTR activity was minimal (3.45 
      +/- 0.25 muA/cm(2)) and not enhanced with ETI (5.73 +/- 0.48 muA/cm(2)), aligning with 
      the individual's clinical evaluation as a non-responder to ETI. Conclusion: The 
      combination of in silico simulations and in vitro theratyping in patient-derived 
      cell models can effectively assess CFTR modulator efficacy for individuals with 
      non-classical CF manifestations or rare CFTR mutations, guiding personalized 
      treatment strategies and optimizing clinical outcomes.
CI  - Copyright (c) 2023 Allan, Astore, Kardia, Wong, Fawcett, Bell, Visser, Chen, 
      Griffith, Jaffe, Sivam, Vittorio, Kuyucak and Waters.
FAU - Allan, Katelin M
AU  - Allan KM
AD  - School of Clinical Medicine, Discipline of Paediatrics and Child Health, Faculty 
      of Medicine and Health, UNSW Sydney, Sydney, NSW, Australia.
AD  - Molecular and Integrative Cystic Fibrosis Research Centre, UNSW Sydney, Sydney, 
      NSW, Australia.
AD  - School of Biomedical Sciences, Faculty of Medicine and Health, UNSW Sydney, 
      Sydney, NSW, Australia.
FAU - Astore, Miro A
AU  - Astore MA
AD  - School of Physics, The University of Sydney, Sydney, NSW, Australia.
FAU - Kardia, Egi
AU  - Kardia E
AD  - School of Clinical Medicine, Discipline of Paediatrics and Child Health, Faculty 
      of Medicine and Health, UNSW Sydney, Sydney, NSW, Australia.
AD  - Molecular and Integrative Cystic Fibrosis Research Centre, UNSW Sydney, Sydney, 
      NSW, Australia.
AD  - School of Biomedical Sciences, Faculty of Medicine and Health, UNSW Sydney, 
      Sydney, NSW, Australia.
FAU - Wong, Sharon L
AU  - Wong SL
AD  - School of Clinical Medicine, Discipline of Paediatrics and Child Health, Faculty 
      of Medicine and Health, UNSW Sydney, Sydney, NSW, Australia.
AD  - Molecular and Integrative Cystic Fibrosis Research Centre, UNSW Sydney, Sydney, 
      NSW, Australia.
AD  - School of Biomedical Sciences, Faculty of Medicine and Health, UNSW Sydney, 
      Sydney, NSW, Australia.
FAU - Fawcett, Laura K
AU  - Fawcett LK
AD  - School of Clinical Medicine, Discipline of Paediatrics and Child Health, Faculty 
      of Medicine and Health, UNSW Sydney, Sydney, NSW, Australia.
AD  - Molecular and Integrative Cystic Fibrosis Research Centre, UNSW Sydney, Sydney, 
      NSW, Australia.
AD  - School of Biomedical Sciences, Faculty of Medicine and Health, UNSW Sydney, 
      Sydney, NSW, Australia.
AD  - Department of Respiratory Medicine, Sydney Children's Hospital, Sydney, NSW, 
      Australia.
FAU - Bell, Jessica L
AU  - Bell JL
AD  - School of Clinical Medicine, Discipline of Paediatrics and Child Health, Faculty 
      of Medicine and Health, UNSW Sydney, Sydney, NSW, Australia.
AD  - Children's Cancer Institute, UNSW Sydney, Sydney, NSW, Australia.
FAU - Visser, Simone
AU  - Visser S
AD  - Department of Respiratory Medicine, Royal Prince Alfred Hospital, Sydney, NSW, 
      Australia.
FAU - Chen, Po-Chia
AU  - Chen PC
AD  - School of Physics, The University of Sydney, Sydney, NSW, Australia.
FAU - Griffith, Renate
AU  - Griffith R
AD  - School of Natural Sciences (Chemistry), University of Tasmania, Hobart, TAS, 
      Australia.
FAU - Jaffe, Adam
AU  - Jaffe A
AD  - School of Clinical Medicine, Discipline of Paediatrics and Child Health, Faculty 
      of Medicine and Health, UNSW Sydney, Sydney, NSW, Australia.
AD  - Molecular and Integrative Cystic Fibrosis Research Centre, UNSW Sydney, Sydney, 
      NSW, Australia.
AD  - Department of Respiratory Medicine, Sydney Children's Hospital, Sydney, NSW, 
      Australia.
FAU - Sivam, Sheila
AU  - Sivam S
AD  - Department of Respiratory Medicine, Royal Prince Alfred Hospital, Sydney, NSW, 
      Australia.
FAU - Vittorio, Orazio
AU  - Vittorio O
AD  - School of Biomedical Sciences, Faculty of Medicine and Health, UNSW Sydney, 
      Sydney, NSW, Australia.
AD  - Children's Cancer Institute, UNSW Sydney, Sydney, NSW, Australia.
FAU - Kuyucak, Serdar
AU  - Kuyucak S
AD  - School of Physics, The University of Sydney, Sydney, NSW, Australia.
FAU - Waters, Shafagh A
AU  - Waters SA
AD  - School of Clinical Medicine, Discipline of Paediatrics and Child Health, Faculty 
      of Medicine and Health, UNSW Sydney, Sydney, NSW, Australia.
AD  - Molecular and Integrative Cystic Fibrosis Research Centre, UNSW Sydney, Sydney, 
      NSW, Australia.
AD  - School of Biomedical Sciences, Faculty of Medicine and Health, UNSW Sydney, 
      Sydney, NSW, Australia.
AD  - Department of Respiratory Medicine, Sydney Children's Hospital, Sydney, NSW, 
      Australia.
LA  - eng
PT  - Journal Article
DEP - 20230601
PL  - Switzerland
TA  - Front Mol Biosci
JT  - Frontiers in molecular biosciences
JID - 101653173
PMC - PMC10267335
OTO - NOTNLM
OT  - CFTR
OT  - airway epithelial cell models
OT  - c.3873G>C
OT  - cystic fibrosis
OT  - modulators
OT  - molecular dynamics
OT  - personalized medicine
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- 2023/06/16 06:42
MHDA- 2023/06/16 06:43
PMCR- 2023/01/01
CRDT- 2023/06/16 04:25
PHST- 2023/01/23 00:00 [received]
PHST- 2023/05/15 00:00 [accepted]
PHST- 2023/06/16 06:43 [medline]
PHST- 2023/06/16 06:42 [pubmed]
PHST- 2023/06/16 04:25 [entrez]
PHST- 2023/01/01 00:00 [pmc-release]
AID - 1148501 [pii]
AID - 10.3389/fmolb.2023.1148501 [doi]
PST - epublish
SO  - Front Mol Biosci. 2023 Jun 1;10:1148501. doi: 10.3389/fmolb.2023.1148501. 
      eCollection 2023.