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Cited by 59Cystic Fibrosis Research AdvancesGenetic and Kidney Cyst DiseasesGenomics and Rare Diseases

The CFTR 3849+10kbC->T and 2789+5G->A alleles are associated with a mild CF phenotype

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Duguépéroux, I., De Braekeleer, M.·2005·European Respiratory Journal
DOI 10.1183/09031936.05.10100004
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Abstract

Most cystic fibrosis (CF) transmembrane receptor mutations are rare. The French CF Registry offers an opportunity to study the genotype–phenotype relationship of these rare alleles. Since 1992, 39 CF patients carrying one copy of the 3849+10kbC->T mutation and 88 the 2789+5G->A allele have been seen at least once in a CF care centre. Among them, 16 carrying the 3849+10kbC->T/ΔF508 genotype and 34 with the 2789+5G->A/ΔF508 genotype were seen in 2000. Their age at diagnosis, sweat chloride concentration, anthropometric and lung function results, and clinical aspects were compared with those homozygous for the ΔF508 mutation matched for sex, age and CF care centre. Major differences, most of them statistically significant, in the age at diagnosis, prevalence of pancreatic insufficiency, and other clinical signs, anthropometric and lung function measures were observed between both compound heterozygote groups and their matched ΔF508/ΔF508 groups. The mean sweat chloride concentration was also lower (close to normal values) among 3849+10kbC->T/ΔF508 patients, but not among 2789+5G->A/ΔF508 patients. In conclusion, both mutations studied here are associated with a milder course of cystic fibrosis disease. The 3849+10kbC->T and 2789+5G->A alleles are splice site mutations, leading to abnormal mRNA; however, a small amount of normally spliced transcripts can also be detected. The presence of these small amounts of normal cystic fibrosis transmembrane receptor protein in these cystic fibrosis patients is likely to be responsible for the milder severity of disease and a better life expectancy.

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Crossref · 10.1183/09031936.05.10100004

Cites

31 of 31 references verified0 citation errors · 0 not checkable

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  • The 3849+10kbC>T CFTR mutation creates a novel donor splice site inside intron 22, leading to insertion of an 84-nucleotide cryptic exon.

    “The 3849+10kbC>T mutation creates a novel donor splice site inside intron 22 of the CFTR gene, leading to the insertion of the new cryptic exon of 84 nucleotides, which results in an in-frame stop codon and consequent production of a truncated non-functional CFTR protein32,33.”

    From Allele specific repair of splicing mutations in cystic fibrosis through AsCas12a genome editing (2019) · cites this paper as [33]

    The Discussion (page not provided) describes the 3849+10kbC>T mutation as involving intron 19 and creating an alternative splice acceptor site, contrary to the claimed donor site in intron 22. Our copy does not mention an 84-nucleotide cryptic exon. (LLM, conf=0.86)

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  • The 3849+10kbC>T mutation generates inclusion of a cryptic exon of 84 nucleotides in CFTR mature mRNA, which is translated into a truncated defective anion channel.

    “This genetic variant generates the inclusion of a cryptic exon of 84 nucleotides in the CFTR mature mRNA, which is translated into a truncated defective anion channel33.”

    From Allele specific repair of splicing mutations in cystic fibrosis through AsCas12a genome editing (2019) · cites this paper as [33]

    The Discussion (page not available) says the 3849+10kbC>T mutation creates an alternative splice acceptor site and leads to abnormal mRNA. It does not specify inclusion of an 84-nucleotide cryptic exon or say that the abnormal mRNA produces a truncated, defective anion channel. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • CFTR modulators are associated with side effects and strongly depend on the residual correct splicing of mutant CFTR, which is extremely reduced and variable among patients.

    “these drugs are associated with side effects and strongly depend on the residual correct splicing of mutant CFTR, which is extremely reduced and variable among patients30–33.”

    From Allele specific repair of splicing mutations in cystic fibrosis through AsCas12a genome editing (2019) · cites this paper as [33]

    The Discussion (page not provided) reports that the two splice-site mutations produce normally spliced transcripts at only 4–8% of normal levels. It does not address CFTR modulator side effects, whether the drugs depend on residual correct splicing, or whether that splicing varies among patients. Its mention of variation concerns the comparison group's clinical results, not splicing. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • The 3849+10kbC>T mutation results in an in-frame stop codon and truncated non-functional CFTR protein.

    “which results in an in-frame stop codon and consequent production of a truncated non-functional CFTR protein32,33.”

    From Allele specific repair of splicing mutations in cystic fibrosis through AsCas12a genome editing (2019) · cites this paper as [33]

    The Discussion (page unavailable) says 3849+10kbC>T is a splice-site mutation that produces abnormal mRNA. It does not state that the abnormal transcript contains an in-frame stop codon or produces a truncated, non-functional protein; it also reports small amounts of normally spliced transcript and normal CFTR protein. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • CFTR modulators (i.e. potentiator VX-770, Kalydeco, Vertex) are used in clinic also for CF patients carrying the splicing mutations of this study.

    “Even though CFTR modulators (i.e. potentiator VX-770, Kalydeco, Vertex) are used in clinic also for CF patients carrying the splicing mutations of this study”

    From Allele specific repair of splicing mutations in cystic fibrosis through AsCas12a genome editing (2019) · cites this paper as [33]

    The Discussion identifies 3849+10kbC→T and 2789+5G→A as splice-site mutations and discusses their clinical phenotype, but not treatment with CFTR modulators. Searches for VX-770, Kalydeco, and modulator treatment found no passage in our copy addressing whether patients with these mutations receive them in clinic. The retrieved passages have no page numbers. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

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Cites

Flagged first, then by citations

2 of the 33 references couldn’t be matched to a known paper.

Research works printed but not linked: 5

  1. De Braekeleer M, Bellis G. Observatoire national de la mucoviscidose (ONM): structure de l'observatoire et re ´sultats de l'enque ˆte 1999 [Observatoire national de la mucoviscidose (ONM): structure of the registry and results from the 1999 enquiry]. Re ´fe ´rence Mucoviscidose 2001; 6: 42-48.
  2. Dugue ´pe ´roux I, Bellis G, Fe ´rec C, Gillet D, Scotet V, De Braekeleer M. Relationship between genotype and pheno- type for the CFTR gene W846X mutation. J Med Genet 2002; 39: E32.
  3. Estivill X, Bancells C, Ramos C, Biomed CF mutation Analysis Consortium. Geographic distribution and regio- nal origin of 272 cystic fibrosis mutations in European populations. Hum Mutat 1997; 10: 135-154.
  4. Stern RC, Doershuk CF, Drumm ML. 3839+10kb C-.T mutation and disease severity in cystic fibrosis. Lancet 1995; 346: 274-276.
  5. Claustres M, Guittard C, Bozon D, et al. Spectrum of CFTR mutations in cystic fibrosis and in congenital absence of the vas deferens in France. Hum Mutat 2000; 16: 143-156.

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Authors
Duguépéroux, I., & De Braekeleer, M.
Venue
European Respiratory Journal
Publisher
European Respiratory Society (ERS)
Published
2005-03
Volume
25
Issue
3
Pages
468-473
ISSN
  • 0903-1936 (ISSN-L)
  • 1399-3003
DOI
10.1183/09031936.05.10100004
OpenAlex
W1967064450
Cited by
59
References
33
Citations by year
2026: 4 · 2025: 3 · 2024: 4 · 2023: 3 · 2022: 4 · 2021: 4 · 2020: 3 · 2019: 3 · 2018: 1 · 2017: 7 · 2015: 4 · 2014: 1 · 2013: 1 · 2012: 4
FWCI
1.86
Type
journal article
Language
en
Open access
Locations
  • European Respiratory Journal (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cystic Fibrosis Research Advances
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
Keywords
cystic fibrosis, CFTR, splice site mutation, deltaF508, genotype-phenotype correlation, compound heterozygosity, sweat chloride, pancreatic insufficiency, lung function, age at diagnosis, mRNA splicing
MeSH terms
Adult, Alleles, Cystic Fibrosis, Female, France, Genotype, Humans, Life Expectancy, Male, Exocrine Pancreatic Insufficiency, Phenotype, Registries, Comorbidity, Age of Onset, Age Distribution, Sex Distribution, Cystic Fibrosis Transmembrane Conductance Regulator, Body Size

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