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Novel frameshift variant of the CFTR gene: S511Lfs*2 from phenotype to molecular predictions

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Abstract

Cystic fibrosis (CF) is a genetic disease caused by variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. There are over 2,000 different pathogenic and non-pathogenic variants described in association with a broad clinical heterogeneity. In this work, we identified a novel variant S511Lfs*2 in CFTR gene that has not been reported in patients with CF. The patient was a female genotyped with c.1000C>T (legacy name: R334W) variant (pathogenic, CF-causing) and the novel variant (S511Lfs*2). We verified the amino acid sequence, the protein structure, and predicted the pathogenicity employing computational analysis. Our findings showed that S511Lfs*2 is a frameshift variant and suggest that it is associated with severe CF phenotype, as it leads to a lack of CFTR protein synthesis, and consequently the loss of its functional activity.

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Acknowledgements

The authors are grateful to Arnaldo Zaha for providing the laboratory facilities to carry out the allele-specific cloning assay of the novel variant.

Funding

The study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES – Finance Code 001) and Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS, 1260-2551/13-0).

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Authors and Affiliations

  1. Programa de Pós-Graduação em Biologia Celular e Molecular, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil

    Thaiane Rispoli, Mayara Jorgens Prado & Maria Lucia Rossetti

  2. Centro de Desenvolvimento Científico e Tecnológico, Secretaria da Saúde do Estado do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil

    Thaiane Rispoli, Grazielle Motta Rodrigues, Mayara Jorgens Prado, Tarciana Grandi & Cláudia Maria Dornelles da Silva

  3. Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil

    Grazielle Motta Rodrigues

  4. Hospital São Lucas da PUCRS, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil

    Leonardo Araújo Pinto

  5. Serviço de Fibrose Cística - Adultos, Serviço de Pneumologia, Hospital São Lucas da PUCRS, Porto Alegre, Rio Grande do Sul, Brazil

    Marcelo Tadday Rodrigues & Cynthia Rocha Dullius

  6. Instituto de Ciências Biológicas, Universidade de Passo Fundo, Passo Fundo, Rio Grande do Sul, Brazil

    José Eduardo Vargas

  7. Programa de Pós-Graduação em Pediatria e Saúde da Criança, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil

    Maurício Menegatti Rigo

  8. Programa de Pós-Graduação em Biologia Celular e Molecular Aplicada à Saúde, Universidade Luterana do Brazil, Canoas, Rio Grande do Sul, Brazil

    Maria Lucia Rossetti

Authors
  1. Thaiane Rispoli
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  2. Grazielle Motta Rodrigues
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  3. Mayara Jorgens Prado
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  4. Leonardo Araújo Pinto
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  5. Marcelo Tadday Rodrigues
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  6. Cynthia Rocha Dullius
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  7. Tarciana Grandi
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  8. Cláudia Maria Dornelles da Silva
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  9. José Eduardo Vargas
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  10. Maurício Menegatti Rigo
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  11. Maria Lucia Rossetti
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Contributions

Thaiane Rispoli and Grazielle Rodrigues: designed the experiments, performed the experiments, analysed, and interpreted the data, drafted the manuscript, read, and approved the final manuscript. Mayara J. Prado: designed, drafted, and performed the in vitro allele-specific cloning, revised the manuscript, read, and approved the final manuscript. Leonardo Araújo Pinto, Marcelo Tadday Rodrigues, Cynthia Rocha Dullius: collected phenotypic data from patients, revised the manuscript, read, and approved the final manuscript. Tarciana Grandi, Cláudia Maria Dornelles da Silva, José Eduardo Vargas: revised the manuscript, read, and approved the final manuscript. Maurício Menegatti Rigo, Maria Lucia Rossetti: supervised the study, read, and approved the final manuscript.

Corresponding author

Correspondence to Thaiane Rispoli.

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Conflict of interest

Authors declared no conflict of interest.

Ethical approval

The subject enrolled in the study was a volunteer from the CF Reference Center (Hospital São Lucas da PUCRS). The study was conducted according to the 1964 Helsinki declaration and all procedures involving human subjects were approved by the Local Ethics Committee of the Hospital São Lucas – PUCRS and Secretaria da Saúde do Estado do Rio Grande do Sul.

Informed consent

Written informed consent was obtained from the subject enrolled in the study. Declaration of consent in the study from the participant is available from the correspondence author.

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Thaiane Rispoli and Grazielle Motta Rodrigues have contributed equally to the work.

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Rispoli, T., Rodrigues, G.M., Prado, M.J. et al. Novel frameshift variant of the CFTR gene: S511Lfs*2 from phenotype to molecular predictions. Mol Biol Rep 47, 6463–6469 (2020). https://doi.org/10.1007/s11033-020-05677-z

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  • DOI: https://doi.org/10.1007/s11033-020-05677-z

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