PMID- 35008443
OWN - NLM
STAT- MEDLINE
DCOM- 20220128
LR  - 20220128
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 23
IP  - 1
DP  - 2021 Dec 21
TI  - Rare Trafficking CFTR Mutations Involve Distinct Cellular Retention Machineries 
      and Require Different Rescuing Strategies.
LID - 10.3390/ijms23010024 [doi]
LID - 24
AB  - Most of the ~2100 CFTR variants so far reported are very rare and still 
      uncharacterized regarding their cystic fibrosis (CF) disease liability. Since 
      some may respond to currently approved modulators, characterizing their defect 
      and response to these drugs is essential. Here we aimed characterizing the defect 
      associated with four rare missense (likely Class II) CFTR variants and assess 
      their rescue by corrector drugs. We produced CFBE cell lines stably expressing 
      CFTR with W57G, R560S, H1079P and Q1100P, assessed their effect upon CFTR 
      expression and maturation and their rescue by VX-661/VX-445 correctors. Results 
      were validated by forskolin-induced swelling assay (FIS) using intestinal 
      organoids from individuals bearing these variants. Finally, knock-down (KD) of 
      genes previously shown to rescue F508del-CFTR was assessed on these mutants. 
      Results show that all the variants preclude the production of mature CFTR, 
      confirming them as Class II mutations. None of the variants responded to VX-661 
      but the combination rescued H1079P- and Q1100P-CFTR. The KD of factors that 
      correct F508del-CFTR retention only marginally rescued R560S- and H1079P-CFTR. 
      Overall, data evidence that Class II mutations induce distinct molecular defects 
      that are neither rescued by the same corrector compounds nor recognized by the 
      same cellular machinery, thus requiring personalized drug discovery initiatives.
FAU - Ramalho, Sofia S
AU  - Ramalho SS
AUID- ORCID: 0000-0002-7554-9802
AD  - BioISI-Biosystems & Integrative Sciences Institute, Faculty of Sciences, 
      University of Lisboa, Campo Grande, C8 bdg, 1749-016 Lisboa, Portugal.
FAU - Silva, Iris A L
AU  - Silva IAL
AUID- ORCID: 0000-0002-8062-5558
AD  - BioISI-Biosystems & Integrative Sciences Institute, Faculty of Sciences, 
      University of Lisboa, Campo Grande, C8 bdg, 1749-016 Lisboa, Portugal.
FAU - Amaral, Margarida D
AU  - Amaral MD
AD  - BioISI-Biosystems & Integrative Sciences Institute, Faculty of Sciences, 
      University of Lisboa, Campo Grande, C8 bdg, 1749-016 Lisboa, Portugal.
FAU - Farinha, Carlos M
AU  - Farinha CM
AUID- ORCID: 0000-0002-5467-1710
AD  - BioISI-Biosystems & Integrative Sciences Institute, Faculty of Sciences, 
      University of Lisboa, Campo Grande, C8 bdg, 1749-016 Lisboa, Portugal.
LA  - eng
GR  - UIDB/04046/2020 and UIDP/04046/2020/Fundacao para a Ciencia e Tecnologia/
GR  - FARINH19I0/Cystic Fibrosis Foundation/
PT  - Journal Article
DEP - 20211221
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (Benzodioxoles)
RN  - 0 (CFTR protein, human)
RN  - 0 (Indoles)
RN  - 0 (Pyrazoles)
RN  - 0 (Pyridines)
RN  - 0 (Pyrrolidines)
RN  - 0 (tezacaftor)
RN  - 126880-72-6 (Cystic Fibrosis Transmembrane Conductance Regulator)
RN  - RRN67GMB0V (elexacaftor)
SB  - IM
MH  - Benzodioxoles/pharmacology
MH  - Cell Line
MH  - Cystic Fibrosis/drug therapy/genetics
MH  - Cystic Fibrosis Transmembrane Conductance Regulator/*genetics
MH  - Female
MH  - Humans
MH  - Indoles/pharmacology
MH  - Male
MH  - Mutation/*genetics
MH  - Pyrazoles/pharmacology
MH  - Pyridines/pharmacology
MH  - Pyrrolidines/pharmacology
PMC - PMC8744605
OTO - NOTNLM
OT  - cystic fibrosis
OT  - intestinal organoids
OT  - personalized medicine
OT  - protein trafficking
OT  - rare mutations
OT  - revertants
COIS- The authors declare no conflict of interest.
EDAT- 2022/01/12 06:00
MHDA- 2022/01/29 06:00
PMCR- 2021/12/21
CRDT- 2022/01/11 01:02
PHST- 2021/11/22 00:00 [received]
PHST- 2021/12/17 00:00 [revised]
PHST- 2021/12/18 00:00 [accepted]
PHST- 2022/01/11 01:02 [entrez]
PHST- 2022/01/12 06:00 [pubmed]
PHST- 2022/01/29 06:00 [medline]
PHST- 2021/12/21 00:00 [pmc-release]
AID - ijms23010024 [pii]
AID - ijms-23-00024 [pii]
AID - 10.3390/ijms23010024 [doi]
PST - epublish
SO  - Int J Mol Sci. 2021 Dec 21;23(1):24. doi: 10.3390/ijms23010024.