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Detalhes Referência

Tipo
Artigos em Revista

Tipo de Documento
Artigo Completo

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

Participantes na publicação
Nikhil T. Awatade (Author)
Sofia Ramalho (Author)
Iris A.L. Silva (Author)
Verónica Felício (Author)
Hugo M. Botelho (Author)
BioISI - Biosystems & Integrative Sciences Institute
Dep. Química e Bioquímica
Eyleen de Poel (Author)
Annelotte Vonk (Author)
Jeffrey M. Beekman (Author)
Carlos M. Farinha (Author)
Dep. Química e Bioquímica
BioISI
Margarida D. Amaral (Author)
Dep. Química e Bioquímica
BioISI

Resumo
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.\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\n\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\nMETHODS:\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\nIntestinal 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.\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\n\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\nRESULTS:\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\nOur results show that: R560S does not affect CFTR mRNA splicing; R560S affects CFTR protein processing, totally abrogating the production of its mature form; R560S-CFTR evidences no function as a Cl- channel; and none of the modulators tested rescued R560S-CFTR processing or function.\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\n\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\nCONCLUSION:\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\nAltogether, these results indicate that R560S is a class II mutation. However, unlike F508del, it cannot be rescued by any of the CFTR modulators tested.

Data de Publicação
2019-03

Suporte
Journal of Cystic Fibrosis

Identificadores da Publicação
ISSN - 1569-1993

Editora
Elsevier BV

Volume
18
Fascículo
2

Número de Páginas
7
Página Inicial
182
Página Final
189

Identificadores do Documento
URL - http://dx.doi.org/10.1016/j.jcf.2018.07.001
DOI - https://doi.org/10.1016/j.jcf.2018.07.001

Identificadores de Qualidade
SCIMAGO Q1 (2020) - 2.049 - Pulmonary and Respiratory Medicine
SCIMAGO Q1 (2020) - 2.049 - Pediatrics, Perinatology and Child Health
Web Of Science Q1 (2020) - 5.482 - RESPIRATORY SYSTEM - SCIE
SCOPUS Q1 (2019) - 6.6 - Pediatrics, Perinatology and Child Health
Web Of Science Q1 (2020) - 5.482 - RESPIRATORY SYSTEM - SCIE
SCIMAGO Q1 (2020) - 2.049 - Pediatrics, Perinatology and Child Health
SCOPUS Q1 (2019) - 6.6 - Pulmonary and Respiratory Medicine

Keywords
Ex vivo biomarkers Intestinal organoids Rare mutations R560S CFTR CFTR modulators


Exportar referência

APA
Nikhil T. Awatade, Sofia Ramalho, Iris A.L. Silva, Verónica Felício, Hugo M. Botelho, Eyleen de Poel, Annelotte Vonk, Jeffrey M. Beekman, Carlos M. Farinha, Margarida D. Amaral, (2019). R560S: A class II CFTR mutation that is not rescued by current modulators. Journal of Cystic Fibrosis, 18, 182-189. ISSN 1569-1993. eISSN . http://dx.doi.org/10.1016/j.jcf.2018.07.001

IEEE
Nikhil T. Awatade, Sofia Ramalho, Iris A.L. Silva, Verónica Felício, Hugo M. Botelho, Eyleen de Poel, Annelotte Vonk, Jeffrey M. Beekman, Carlos M. Farinha, Margarida D. Amaral, "R560S: A class II CFTR mutation that is not rescued by current modulators" in Journal of Cystic Fibrosis, vol. 18, pp. 182-189, 2019. 10.1016/j.jcf.2018.07.001

BIBTEX
@article{39284, author = {Nikhil T. Awatade and Sofia Ramalho and Iris A.L. Silva and Verónica Felício and Hugo M. Botelho and Eyleen de Poel and Annelotte Vonk and Jeffrey M. Beekman and Carlos M. Farinha and Margarida D. Amaral}, title = {R560S: A class II CFTR mutation that is not rescued by current modulators}, journal = {Journal of Cystic Fibrosis}, year = 2019, pages = {182-189}, volume = 18 }