ArticleHuman mutation2008
Localization studies of rare missense mutations in cystic fibrosis transmembrane conductance regulator (CFTR) facilitate interpretation of genotype-phenotype relationships.
Article in Human mutation, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 45 citations in OpenAlex.
- Population-based, first-tier genomic newborn screening in the maternity ward.Nature medicine · 2025Article
- Article
- Advances in the Study of Common and RareJournal of personalized medicine · 2024Review
- Molecular structures reveal synergistic rescue of Δ508 CFTR by Trikafta modulators.Science (New York, N.Y.) · 2022Article
- Advances in Preclinical In Vitro Models for the Translation of Precision Medicine for Cystic Fibrosis.Journal of personalized medicine · 2022Review
- Functional and Pharmacological Characterization of the Rare CFTR Mutation W361R.Frontiers in pharmacology · 2020Article
- Novel, rare and common pathogenic variants in the CFTR gene screened by high-throughput sequencing technology and predicted by in silico tools.Scientific reports · 2019Article
- Capitalizing on the heterogeneous effects of CFTR nonsense and frameshift variants to inform therapeutic strategy for cystic fibrosis.PLoS genetics · 2018Article
- Targeted sequencing reveals complex, phenotype-correlated genotypes in cystic fibrosis.BMC medical genomics · 2018Article
- A sequence upstream of canonical PDZ-binding motif within CFTR COOH-terminus enhances NHERF1 interaction.American journal of physiology. Lung cellular and molecular physiology · 2016Article
- Targeted mutation screening panels expose systematic population bias in detection of cystic fibrosis risk.Genetics in medicine : official journal of the American College of Medical Genetics · 2016Article
- Restoration of NBD1 thermal stability is necessary and sufficient to correct ∆F508 CFTR folding and assembly.Journal of molecular biology · 2015Article
- Cystic fibrosis genetics: from molecular understanding to clinical application.Nature reviews. Genetics · 2015Review
- Experimental assessment of splicing variants using expression minigenes and comparison with in silico predictions.Human mutation · 2014Article
- Melanocortin 3 receptor has a 5' exon that directs translation of apically localized protein from the second in-frame ATG.Molecular endocrinology (Baltimore, Md.) · 2014Article
- Complement yourself: Transcomplementation rescues partially folded mutant proteins.Biophysical reviews · 2014Article
- Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene.Nature genetics · 2013Article
- Gout-causing Q141K mutation in ABCG2 leads to instability of the nucleotide-binding domain and can be corrected with small molecules.Proceedings of the National Academy of Sciences of the United States of America · 2013Article
- Requirements for efficient correction of ΔF508 CFTR revealed by analyses of evolved sequences.Cell · 2012Article
- Genotype-phenotype correlation in cystic fibrosis patients bearing [H939R;H949L] allele.Genetics and molecular biology · 2011Article
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
We have been investigating the functional consequences of rare disease-associated amino acid substitutions in the cystic fibrosis transmembrane conductance regulator (CFTR). Mutations of the arginine residue at codon 1070 have been associated with different disease consequences; R1070P and R1070Q with "severe" pancreatic insufficient cystic fibrosis (CF) and R1070W with "mild" pancreatic sufficient CF or congenital bilateral absence of the vas deferens. Intriguingly, CFTR bearing each of these mutations is functional when expressed in nonpolarized cells. To determine whether R1070 mutations cause disease by affecting CFTR localization, we created polarized Madin Darby canine kidney (MDCK) cell lines that express either wild-type or mutant CFTR from the same genomic integration site. Confocal microscopy and biotinylation studies revealed that R1070P was not inserted into the apical membrane, R1070W was inserted at levels reduced from wild-type while R1070Q was present in the apical membrane at levels comparable to wild-type. The abnormal localization of CFTR bearing R1070P and R1070W was consistent with deleterious consequences in patients; however, the profile of CFTR R1070Q was inconsistent with a "severe" phenotype. Reanalysis of 16 patients with the R1070Q mutation revealed that 11 carried an in cis nonsense mutation, S466X. All 11 patients carrying the complex allele R1070Q-S466X had severe disease, while 4 out of 5 patients with R1070Q had "mild" disease, thereby reconciling the apparent discrepancy between the localization studies of R1070Q and the phenotype of patients bearing this mutation. Our results emphasize that localization studies in relevant model systems can greatly assist the interpretation of the disease-causing potential of rare missense mutations.
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