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Health Characteristics of Patients with Cystic Fibrosis whose Genotype Includes a Variant of the Nucleotide Sequence c.3140-16T>A and Functional Analysis of this Variant

1
Research Centre for Medical Genetics, 115522 Moscow, Russia
2
Faculty of Pediatrics, Perm State Medical University, 614990 Perm, Russia
*
Author to whom correspondence should be addressed.
Academic Editor: Yuri A. Motorin
Genes 2021, 12(6), 837; https://doi.org/10.3390/genes12060837
Received: 22 April 2021 / Revised: 17 May 2021 / Accepted: 25 May 2021 / Published: 28 May 2021
(This article belongs to the Section Human Genomics and Genetic Diseases)
Cystic fibrosis (CF) is the most common monogenic autosomal recessive disease, associated with pathogenic variants in the CFTR gene. The splicing variant c.3140-16T>A (3272-16T>A) has been described previously and, according to the Russian CF Patients Registry, occurs with a frequency of 0.34%. The phenotypic features of CF patients with the c.3140-16T>A variant were compared with those of patients with the genotype F508del/F508del. Patients with the allele c.3140-16T>A had higher average age and age at diagnosis, and the allele was present in a greater proportion of adults. Patients carrying the c.3140-16T>A allele were characterised by better physical development indicators, both in adults and in children, had preserved pancreatic function, as well as the absence of a number of complications, and required pancreatic enzyme replacement therapy less often than patients with the F508del/F508del genotype. Sweat test values also were lower in patients with the c.3140-16T>A genotype. According to the results of clinical and laboratory studies, the phenotype of patients with the genetic variant c.3140-16T>A can be considered “mild”. Functional CFTR protein activity in the presence of c.3140-16T>A was evaluated using intestinal current measurements (ICM) and the forskolin-induced swelling assay on organoids obtained from patients’ rectal biopsies. c.3140-16T>A had high residual CFTR channel activity and was amenable to effective pharmacological correction with thea VX-770 potentiator. To evaluate the effect of the variant on CFTR pre-mRNA splicing we performed a minigene assay, as well as RT-PCR analysis of RNA isolated from the nasal epithelium and rectal biopsy of patients. We showed that the c.3140-16T>A variant creates a novel acceptor AG dinucleotide within CFTR intron 19, resulting in a 14-nucleotide extension of exon 20. This frameshift produces a premature termination codon and triggers mRNA degradation by the nonsense-mediated decay (NMD) mechanism. Moreover, we observed that the c.3140-16T>A allele could produce a residual amount of normally spliced transcript, thus explaining the patient’s mild phenotype. View Full-Text
Keywords: c.3140-16T>A variant; CFTR; cystic fibrosis c.3140-16T>A variant; CFTR; cystic fibrosis
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MDPI and ACS Style

Kondratyeva, E.; Bukharova, T.; Efremova, A.; Melyanovskaya, Y.; Bulatenko, N.; Davydenko, K.; Filatova, A.; Skoblov, M.; Krasovsky, S.; Petrova, N.; Polyakov, A.; Adyan, T.; Amelina, E.; Shadrina, V.; Zhekaite, E.; Zodbinova, A.; Chernyak, A.; Zinchenko, R.; Kutsev, S.; Goldshtein, D. Health Characteristics of Patients with Cystic Fibrosis whose Genotype Includes a Variant of the Nucleotide Sequence c.3140-16T>A and Functional Analysis of this Variant. Genes 2021, 12, 837. https://doi.org/10.3390/genes12060837

AMA Style

Kondratyeva E, Bukharova T, Efremova A, Melyanovskaya Y, Bulatenko N, Davydenko K, Filatova A, Skoblov M, Krasovsky S, Petrova N, Polyakov A, Adyan T, Amelina E, Shadrina V, Zhekaite E, Zodbinova A, Chernyak A, Zinchenko R, Kutsev S, Goldshtein D. Health Characteristics of Patients with Cystic Fibrosis whose Genotype Includes a Variant of the Nucleotide Sequence c.3140-16T>A and Functional Analysis of this Variant. Genes. 2021; 12(6):837. https://doi.org/10.3390/genes12060837

Chicago/Turabian Style

Kondratyeva, Elena, Tatyana Bukharova, Anna Efremova, Yuliya Melyanovskaya, Natalia Bulatenko, Ksenia Davydenko, Alexandra Filatova, Mikhail Skoblov, Stanislav Krasovsky, Nika Petrova, Alexander Polyakov, Tagui Adyan, Elena Amelina, Vera Shadrina, Elena Zhekaite, Aysa Zodbinova, Alexander Chernyak, Rena Zinchenko, Sergei Kutsev, and Dmitry Goldshtein. 2021. "Health Characteristics of Patients with Cystic Fibrosis whose Genotype Includes a Variant of the Nucleotide Sequence c.3140-16T>A and Functional Analysis of this Variant" Genes 12, no. 6: 837. https://doi.org/10.3390/genes12060837

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