CoChat
Sign Up
Cited by 46Cystic Fibrosis Research AdvancesGenetic and Kidney Cyst DiseasesGenomics and Rare Diseases

Cystic fibrosis patients with the 3272-26A>G splicing mutation have milder disease than F508del homozygotes: a large European study

Open access
Amaral, Margarida D, Pacheco, Paula, Beck, Sebastian, Farinha, Carlos M, Penque, Deborah, Nogueira, Paulo, Barreto, Celeste, Lopes, Beatriz +31 more·2001·Journal of Medical Genetics
DOI 10.1136/jmg.38.11.777PMC PMC1734751
Open this paper in CoChat — free account

Abstract

Editor—Cystic fibrosis (CF, MIM 219700) is a common, severe, autosomal recessive disease caused by mutations in the CF transmembrane conductance regulator ( CFTR ) gene cloned in 1989.1-3The disease, characterised by chronic lung disease which is the main cause of morbidity and mortality, pancreatic dysfunction, raised electrolyte levels in sweat, and male infertility, is caused by altered chloride (Cl−) secretion across the apical membrane of epithelial cells.4 There is, however, substantial variability in the clinical manifestations affecting the various organs.4 5 One single mutation, F508del, generally associated with severe disease, accounts for about 70% of CF chromosomes world wide, although with a heterogeneous geographical distribution.5 Patients homozygous for the F508del mutation have the classical severe form of the disease which includes chronic mucous obstruction of the lung and conducting airways, followed by recurrent infections mostly by Pseudomonas aeruginosa (Pa) and Staphylococcus aureus (Sa), exocrine pancreatic insufficiency (PI), resulting in failure to gain weight and height, and raised levels of Cl−, sodium, and potassium in exocrine sweat.5 However, almost 1000 genetic alterations have been detected in the CFTR gene ( CFTR Mutation Database), most presumed to be disease causing mutations. About half of these are amino acid substitutions (missense mutations) and about 20% are splicing mutations. The remainder are nonsense, frameshift (including small deletions and insertions), and a small proportion of promoter mutations. The relationship between genotype, that is, the mutations in the CFTR gene, and the clinical phenotype of CF patients has been difficult to establish, in particular for lung disease. It was previously shown that the 3272-26A>G mutation leads to the creation of an alternative acceptor splice site competing with the normal one during RNA processing and resulting in the occurrence of an alternatively spliced mRNA with 25 extra nucleotides from …

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1136/jmg.38.11.777

Cites

34 of 34 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The 3272-26A>G CFTR mutation creates a new acceptor splice site causing abnormal inclusion of 25 nucleotides within exon 20.

    “The 3242-26A>G is a point mutation that creates a new acceptor splice site causing the abnormal inclusion of 25 nucleotides within exon 2030,31.”

    From Allele specific repair of splicing mutations in cystic fibrosis through AsCas12a genome editing (2019) · cites this paper as [31]

    The paper’s introductory discussion (p. 777) says that 3272-26A>G creates an alternative acceptor splice site and produces mRNA with 25 extra nucleotides from intron 17a. It does not identify exon 20 as the location of their inclusion. The citing sentence also prints the mutation as 3242-26A>G, rather than 3272-26A>G. (LLM, conf=0.88)

    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 [31]

    In “3272-26A>G CAUSES MILD CF” (page not specified), the paper says this mutation permits some normally spliced CFTR mRNA and describes variability in patients’ clinical manifestations. It does not establish that CFTR modulators have side effects or depend on residual correct splicing, and it says quantifying the remaining normal mRNA was still future research rather than showing it was extremely reduced or variable among patients. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • The 3272-26A>G mutation results in mRNA with a frameshift, premature termination codon, and truncated non-functional CFTR protein.

    “The resulting mRNA contains a frameshift in CFTR, producing a premature termination codon and consequent expression of a truncated non-functional CFTR protein.”

    From Allele specific repair of splicing mutations in cystic fibrosis through AsCas12a genome editing (2019) · cites this paper as [31]

    The paper’s introductory passage (page not available in our copy) says the mutation produces an alternatively spliced mRNA with 25 extra nucleotides and a premature stop codon, supporting the frameshift and premature-termination parts of the claim. Its discussion says some normally spliced mRNA remains and produces functional CFTR, but does not establish that the alternatively spliced mRNA is expressed as a truncated, non-functional protein. (LLM, conf=0.86)

    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 [31]

    The paper reports clinical phenotypes of patients with the 3272-26A>G splicing mutation, not their treatment with CFTR modulators. In “3272-26A>G CAUSES MILD CF” (page not specified in our copy), it discusses modulation of splicing only as a possible avenue for future therapies. Searches for VX-770, Kalydeco, potentiators, and clinical treatment found no passage supporting the claimed clinical use. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 3

  1. 5 Welsh M, Tsui LC, Boat TF, Beaudet AL. Cystic fibrosis. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic and molecular basis of inherited disease . 7th ed. New York: McGraw-Hill, 1995:3799-876.
  2. 19 Conway SP, Littlewood JM. Cystic fibrosis clinical scoring systems. In: Dodge JA, Brock DJ, Widdicombe JH, eds. Cystic fibrosis. Current topics . New York: Wiley, 1996:339-58.
  3. 31 Kerem E, Kerem B. Genotype-phenotype correlations in cystic fibrosis. Pediatr Pulmonol 1996; 22 :387-95.

Cited by

Sorted by citations

Related

Authors
Amaral, M. D., Pacheco, P., Beck, S., Farinha, C. M., Penque, D., Nogueira, P., Barreto, C., Lopes, B., Casals, T., Dapena, J., Gartner, S., Vásquez, C., Pérez-Frías, J., Olveira, C., Cabanas, R., Estivill, X., Tzetis, M., Kanavakis, E., Doudounakis, S., Dörk, T., Tümmler, B., Girodon-Boulandet, E., Cazeneuve, C., Goossens, M., Blayau, M., Verlingue, C., Vieira, I., Féréc, C., Claustres, M., Georges, M. D., Clavel, C., Birembaut, P., Hubert, D., Bienvenu, T., Adoun, M., Chomel, J.-C., De Boeck, K., Cuppens, H., & Lavinha, J.
Corresponding author
Amaral, Margarida D
ORCID
Venue
Journal of Medical Genetics
Publisher
BMJ
Published
2001-11-01
Volume
38
Issue
11
Pages
777-783
ISSN
  • 0022-2593 (ISSN-L)
  • 1468-6244
DOI
10.1136/jmg.38.11.777
PMC
PMC1734751
OpenAlex
W2100708093
Cited by
37
References
34
Citations by year
2021: 1 · 2019: 1 · 2018: 2 · 2017: 1 · 2016: 2 · 2014: 1 · 2013: 1 · 2012: 4
FWCI
2.35
Type
journal article
Language
en
Open access
Locations
  • Journal of Medical Genetics (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • HighWire Press Open Archive (submittedVersion)
Funders
British Heart Foundation
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 gene, F508del mutation, splicing mutation, genotype-phenotype correlation, disease severity, alternative splicing, lung disease, exocrine pancreatic insufficiency, Pseudomonas aeruginosa infection
MeSH terms
Alleles, Cystic Fibrosis, DNA, DNA Mutational Analysis, Europe, Female, Genotype, Haplotypes, Homozygote, Humans, Male, Phenotype, Severity of Illness Index, Point Mutation, Sequence Deletion, Alternative Splicing, Cystic Fibrosis Transmembrane Conductance Regulator

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review