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Vol. 63 No. 11: Issue 11

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Complexity of phenotypes induced by p.Asn1303Lys-CFTR correlates with difficulty to rescue and activate this protein

https://doi.org/10.14715/cmb/2017.63.11.18
Raí«d Farhat
EA3808, Université de Poitiers, Pí´le Biologie Santé, France
Ayman El-Seedy
EA3808, Université de Poitiers, Pí´le Biologie Santé, France
Caroline Norez
Laboratoire Signalisation et Transports Ioniques Membranaires, Université de Poitiers/CNRS, France
Hugo Talbot
EA3808, Université de Poitiers, Pí´le Biologie Santé, France
Marie-Claude Pasquet
Centre Hospitalier Universitaire (CHU) de Poitiers, Poitiers, France
Catherine Adolphe
EA3808, Université de Poitiers, Pí´le Biologie Santé, France
Alain Kitzis
EA3808, Université de Poitiers, Pí´le Biologie Santé, France
Véronique Ladevèze
EA3808, Université de Poitiers, Pí´le Biologie Santé, France

Corresponding Author(s) : Véronique Ladevèze

veronique.ladeveze@univ-poitiers.fr

Cellular and Molecular Biology, Vol. 63 No. 11: Issue 11

Abstract

Cystic Fibrosis is the most common recessive autosomal rare disease found in Caucasian. It is caused by mutations on the Cystic Fibrosis Transmembrane Conductance Regulator gene (CFTR) that encodes for a protein located on the apical membrane of epithelial cells. c.3909C>G (p.Asn1303Lys) is one of the most common worldwide mutations located in nucleotide binding domain 2. The effect of the p.Asn1303Lys mutation on misprocessing was studied by immunofluorescence and western blotting analysis in presence and absence of treatment. To evaluate the functionality of potentially rescued p.Asn1303Lys-CFTR, we assessed the channel activity by radioactive iodide efflux. No recovery of the activity was observed in transfected cultured cells treated with VX-809. Thus, our results suggest that multiple drugs may be needed for the treatment of c.3909C>G patients in order to correct and activate p.Asn1303Lys-CFTR as it shows folding and functional defects.

Keywords

Cystic fibrosis p.Asn1303Lys VX-809 Functional impact.
Farhat, R., El-Seedy, A., Norez, C., Talbot, H., Pasquet, M.-C., Adolphe, C., Kitzis, A., & Ladevèze, V. (2017). Complexity of phenotypes induced by p.Asn1303Lys-CFTR correlates with difficulty to rescue and activate this protein. Cellular and Molecular Biology, 63(11), 106–110. https://doi.org/10.14715/cmb/2017.63.11.18
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References
  1. Farra, C., Menassa, R., Awwad, J., et al. 2010. Mutational spectrum of cystic fibrosis in the Lebanese population. J. Cyst. Fibros. 9(6): 406-410.
  2. Osborne, L., Santis, G., Schwarz, M., et al. 1992. Incidence and expression of the N1303K mutation of the cystic fibrosis (CFTR) gene. Hum. Genet. 89(6): 653-658.
  3. Cui, L., Aleksandrov, L., Chang, X.B., et al. 2007. Domain interdependence in the biosynthetic assembly of CFTR. J. Mol. Biol. 365(4): 981-994.
  4. Du, K., Lukacs, G.L., 2009. Cooperative assembly and misfolding of CFTR domains in vivo. Mol. Biol. Cell. 20(7): 1903-1915.
  5. Berger, A., Ikuma, M., Hunt, J., Thomas, P., Welsh, M. 2002. Mutations That Change the Position of the Putative -Phosphate Linker in the Nucleotide Binding Domains of CFTR Alter Channel Gating. J. Biol. Chem. 277: 2125-2131.
  7. Szollosi, A., Vergani, P., Csanády, L. 2010. Involvement of F1296 and N1303 of CFTR in induced-fit conformational change in response to ATP binding at NBD2. J. Gen. Physiol. 136(4): 407-423.
  8. Morral, N., Dörk, T., Llevadot, R., et al. 1996. Haplotype analysis of 94 cystic fibrosis mutations with seven polymorphic CFTR DNA markers. Hum. Mutat. 8(2): 149-159.
  9. Cordovado, S.K., Hendrix, M., Greene, C.N., et al. 2012. CFTR mutation analysis and haplotype associations in CF patients. Mol. Genet. Metab. 105(2): 249-254.
  10. Farhat, R., El-Seedy, A., El-Moussaoui, K., et al. 2015. Multi-physiopathological consequences of the c.1392G>T CFTR mutation revealed by clinical and cellular investigations. Biochem. Cell. Biol. 93(1): 28-37.
  11. Clain, J., Fritsch, J., Lehmann-Che, J., et al. 2001. Two mild cystic fibrosis-associated mutations result in severe cystic fibrosis when combined in cis and reveal a residue important for cystic fibrosis transmembrane conductance regulator processing and function. J. Biol. Chem. 276(12): 9045-9049.
  12. Clain, J., Lehmann-Che, J., Girodon, E., et al. 2005. A neutral variant involved in a complex CFTR allele contributes to a severe cystic fibrosis phenotype. Hum Genet 116(6): 454-460.
  13. Van Goor, F., Hadida, S., Grootenhuis, P.D., et al. 2011. Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809. Proc Natl Acad Sci U S A 108(46): 18843–18848.
  14. Awatade, N.T., Uliyakina, I., Farinha, C.M. et al. 2015. Measurements of Functional Responses in Human Primary Lung Cells as a Basis for Personalized Therapy for Cystic Fibrosis. EBioMedicine 2(2): 147-153.
  15. Laemmli, U.K. 1970. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 227: 680–685.
  16. Norez, C., Heda, G.D., Jensen, T., et al. 2004. Determination of CFTR chloride channel activity and pharmacology using radiotracer flux methods. J Cyst Fibros 3 Suppl 2: 119-121.
  17. Dormer, R.L., Dèrand, R., McNeilly, C.M., et al. 2001. Correction of delF508-CFTR activity with benzo(c)quinolizinium compounds through facilitation of its processing in cystic fibrosis airway cells. J. Cell Sci. 114: 4073-4081.
  18. He, L., Aleksandrov, L.A., Cui, L., Jensen, T.J., Nesbitt, K.L., Riordan, J.R. 2010. Restoration of domain folding and interdomain assembly by second-site suppressors of the DeltaF508 mutation in CFTR. FASEB J 24(8): 3103-3112.
  19. Kleizen, B., van Vlijmen, T., de Jonge, H.R., Braakman, I. 2005. Folding of CFTR is predominantly cotranslational. Mol Cell 20(2): 277-287.
  20. Gregory, R.J., Rich, D.P., Cheng, S.H., et al. Maturation and function of cystic fibrosis transmembrane conductance regulator variants bearing mutations in putative nucleotide-binding domains 1 and 2. Mol Cell Biol 11(8): 3886-3893
  22. Rapino, D., Sabirzhanova, I., Lopes-Pacheco, M., Grover, R., Guggino, W.B., Cebotaru, L. 2015. Rescue of NBD2 mutants N1303K and S1235R of CFTR by small-molecule correctors and transcomplementation. PLoS One 10(3): e0119796.
  23. Sabusap, C., Hong, J.S., McClure, M., Chung, W., Wen, H., Sorscher, E.J. 2014. Impact of palmitoylation on clinically significant mutations characterized by CFTR2. Pediatr Pulmonol 49: 241-242.
  24. Dekkers, J.F., Gogorza Gondra, R.A., Kruisselbrink, E., Vonk, A.M., Janssens, H.M., de Winter-de Groot, K.M., van der Ent, C.K., Beekman, J.M. 2016. Optimal correction of distinct CFTR folding mutants in rectal cystic fibrosis organoids. Eur Respir J 48(2): 451-458.
  25. Hung, L.W., Wang, I.X., Nikaido, K., Liu, P.Q., Ames, G.F., Kim, S.H. 1998. Crystal structure of the ATP-binding subunit of an ABC transporter. Nature 396(6712): 703-707.
  26. Procko, E., Ferrin-O'Connell, I., Ng, S.L., Gaudet, R. 2006. Distinct structural and functional properties of the ATPase sites in an asymmetric ABC transporter. Mol Cell 24(1): 51-62.
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