R560S: A class II CFTR mutation that is not rescued by current modulators

Journal of Cystic Fibrosis : Official Journal of the European Cystic Fibrosis Society
Nikhil T AwatadeMargarida D Amaral

Abstract

New therapies modulating defective CFTR have started to hit the clinic and others are in trial or under development. The endeavour of drug discovery for CFTR protein rescue is however difficult one since over 2000 mutations have been reported. For most of these, especially the rare ones, the associated defects, the respective functional class and their responsiveness to available modulators are still unknown. Our aim here was to characterize the rare R560S mutation using patient-derived materials (rectal biopsies and intestinal organoids) from one CF individual homozygous for this mutation, in parallel with cellular models expressing R560S-CFTR and to assess the functional and biochemical responses to CFTR modulators. Intestinal organoids were prepared from rectal biopsies and analysed by RT-PCR (to assess CFTR mRNA), by Western blot (to assess CFTR protein) and by forskolin-induced swelling (FIS) assay. A novel cell line expressing R560S-CFTR was generated by stably transducing the CFBE parental cell line and used to assess R560S-CFTR processing and function. Both intestinal organoids and the cellular model were used to assess efficacy of CFTR modulators in rescuing this mutation. Our results show that: R560S does not affect C...Continue Reading

References

Jan 1, 1994·American Journal of Respiratory Cell and Molecular Biology·A L CozensD C Gruenert
Jan 29, 1999·Physiological Reviews·D N Sheppard, M J Welsh
Nov 19, 2003·Biochemical and Biophysical Research Communications·Filipa MendesDeborah Penque
Nov 14, 2006·Proceedings of the National Academy of Sciences of the United States of America·Mónica Roxo-RosaMargarida D Amaral
Jul 25, 2009·Molecular Biology of the Cell·Diane E GroveDouglas M Cyr
Oct 23, 2009·Proceedings of the National Academy of Sciences of the United States of America·Fredrick Van GoorPaul Negulescu
Oct 7, 2011·Proceedings of the National Academy of Sciences of the United States of America·Fredrick Van GoorPaul A Negulescu
Sep 6, 2012·British Journal of Pharmacology·Yuemin TianKarl Kunzelmann
Jun 4, 2013·Nature Medicine·Johanna F DekkersJeffrey M Beekman
Jul 31, 2013·Journal of Cystic Fibrosis : Official Journal of the European Cystic Fibrosis Society·Fredrick Van GoorBeth J Hoffman
Nov 19, 2014·Nature Reviews. Genetics·Garry R Cutting
Dec 4, 2014·Journal of Cystic Fibrosis : Official Journal of the European Cystic Fibrosis Society·R DekkersJ M Beekman
Mar 5, 2015·Journal of Cystic Fibrosis : Official Journal of the European Cystic Fibrosis Society·Anabela S RamalhoMargarida D Amaral
May 20, 2015·The New England Journal of Medicine·Claire E WainwrightUNKNOWN TRANSPORT Study Group
Jul 15, 2015·Pharmacology Research & Perspectives·Carlos M FarinhaMargarida D Amaral
Nov 17, 2015·American Journal of Respiratory and Critical Care Medicine·Simon Y GraeberMarcus A Mall
Apr 8, 2016·The Lancet. Respiratory Medicine·Kris De Boeck, Margarida D Amaral
Jun 24, 2016·Science Translational Medicine·Johanna F DekkersJeffrey M Beekman

❮ Previous
Next ❯

Citations

Jan 23, 2019·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Xinying ChenJeng-Haur Chen
Jun 20, 2019·Expert Review of Respiratory Medicine·Kamran M MiahDeborah R Gill
Apr 27, 2019·The European Respiratory Journal·Peter van MourikCornelis K van der Ent
Jul 18, 2019·Scientific Reports·Andrea ArmirottiNicoletta Pedemonte
Mar 11, 2020·Frontiers in Pharmacology·Miquéias Lopes-Pacheco
Nov 17, 2020·European Journal of Medicinal Chemistry·Margarida D Amaral
Jan 12, 2021·Expert Opinion on Drug Delivery·Douweh Leyla Gbian, Abdelwahab Omri
Jun 4, 2019·Journal of Cystic Fibrosis : Official Journal of the European Cystic Fibrosis Society·Carlos M Farinha
Jul 31, 2021·Journal of Experimental Pharmacology·Madalena C PintoMiquéias Lopes-Pacheco
Jul 31, 2020·Biochimica Et Biophysica Acta. Molecular Basis of Disease·Iris A L SilvaMargarida D Amaral

❮ Previous
Next ❯

Related Concepts

Related Feeds

CFTR Mutant Structural Therapy

Over 1700 different mutations in the CFTR genes have been shown to cause cystic fibrosis. Here is the latest research on structural therapy for CFTR mutants.

Related Papers

Journal of Cystic Fibrosis : Official Journal of the European Cystic Fibrosis Society
Johanna F DekkersJeffrey M Beekman
Journal of Cystic Fibrosis : Official Journal of the European Cystic Fibrosis Society
Domenique D Zomer-van OmmenJeffrey M Beekman
© 2022 Meta ULC. All rights reserved