Clinical and Genetic Characteristics of a Patient with Cystic Fibrosis with a Complex Allele [E217G;G509D] and Functional Evaluation of the CFTR Channel.
Elena I KondratyevaYuliya MelyanovskayaAnna EfremovaMariya KrasnovaDiana MokrousovaNataliya BulatenkoNika PetrovaAlexander PolyakovTagui AdyanValeriia A KovalskaiaTatiana Borisovna BukharovaAndrey V MarakhonovRena A ZinchenkoElena ZhekaiteArtem BuhoninDmitry GoldshteinPublished in: Genes (2023)
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.
Keyphrases
- cystic fibrosis
- pseudomonas aeruginosa
- lung function
- small molecule
- biofilm formation
- machine learning
- genome wide
- gene expression
- physical activity
- signaling pathway
- protein protein
- climate change
- ultrasound guided
- rectal cancer
- chronic obstructive pulmonary disease
- human health
- staphylococcus aureus
- escherichia coli
- cancer therapy
- binding protein
- combination therapy