Clinical and Genetic Characteristics of a Patient with Cystic Fibrosis with a Complex Allele [E217G;G509D] and Functional Evaluation of the CFTR Channel

Genes (Basel). 2023 Aug 28;14(9):1705. doi: 10.3390/genes14091705.

Abstract

The intricate nature of complex alleles presents challenges in the classification of CFTR gene mutations, encompassing potential disease-causing, neutral, or treatment-modulating effects. Notably, the complex allele [E217G;G509D] remains absent from international databases, with its pathogenicity yet to be established. Assessing the functionality of apical membrane ion channels in intestinal epithelium employed the intestinal current measurements (ICM) method, using rectal biopsy material. The effectivity of CFTR-targeted therapy was evaluated using a model of intestinal organoids of a patient harboring the genotype F508del/[E217G;G509D]. ICM analysis revealed diminished chloride channel function. Remarkably, [E217G;G509D] presence within intestinal organoids correlated with heightened residual CFTR function. Employing CFTR modulators facilitated the restoration of the functional CFTR protein. This multifaceted study intertwines genetic investigations, functional analyses, and therapeutic interventions, shedding light on the intricate interplay of complex alleles within CFTR mutations. The results highlight the potential of targeted CFTR modulators to restore functional integrity, offering promise for advancing precision treatments in cystic fibrosis management.

Keywords: complex allele; cystic fibrosis (CF); intestinal current measurements (ICM); intestinal organoids; targeted therapy.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Chloride Channels
  • Cystic Fibrosis Transmembrane Conductance Regulator* / genetics
  • Cystic Fibrosis* / drug therapy
  • Cystic Fibrosis* / genetics
  • Genotype
  • Humans

Substances

  • CFTR protein, human
  • Chloride Channels
  • Cystic Fibrosis Transmembrane Conductance Regulator

Grants and funding

The Russian Science Foundation provided funding for this research (grant No. 22-15-00473, “Investigation of the effect of complex alleles of the CFTR gene on the functional activity of the chloride channel for personalized selection of targeted therapy for cystic fibrosis”).