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The CF-Modifying Gene EHF Promotes P.Phe508del-CFTR Residual Function by Altering Protein Glycosylation and Trafficking in Epithelial Cells

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The CF-Modifying Gene EHF Promotes P.Phe508del-CFTR Residual Function by Altering Protein Glycosylation and Trafficking in Epithelial Cells European Journal of Human Genetics (2014) 22, 660–666 & 2014 Macmillan Publishers Limited All rights reserved 1018-4813/14 www.nature.com/ejhg ARTICLE The CF-modifying gene EHF promotes p.Phe508del-CFTR residual function by altering protein glycosylation and trafficking in epithelial cells Frauke Stanke*,1,2, Andrea van Barneveld1,2, Silke Hedtfeld1,2, Stefan Wo¨lfl3, Tim Becker4,5 and Burkhard Tu¨mmler1,2 The three-base-pair deletion c.1521_1523delCTT (p.Phe508del, F508del) in the cystic fibrosis transmembrane conductance regulator (CFTR) is the most frequent disease-causing lesion in cystic fibrosis (CF). The CFTR gene encodes a chloride and bicarbonate channel at the apical membrane of epithelial cells. Altered ion transport of CFTR-expressing epithelia can be used to differentiate manifestations of the so-called CF basic defect. Recently, an 11p13 region has been described as a CF modifier by the North American CF Genetic Modifier Study Consortium. Selecting the epithelial-specific transcription factor EHF (ets homologous factor) as the likely candidate gene on 11p13, we have genotyped two intragenic microsatellites in EHF to replicate the 11p13 finding in the patient cohort of the European CF Twin and Sibling Study. We could observe an association of rare EHF haplotypes among homozygotes for c.1521_1523delCTT in CFTR, which exhibit a CF-untypical manifestation of the CF basic defect such as CFTR-mediated residual chloride secretion and low response to amiloride. We have reviewed transcriptome data obtained from intestinal epithelial samples of homozygotes for c.1521_1523delCTT in CFTR, which were stratified for their EHF genetic background. Transcripts that were upregulated among homozygotes for c.1521_1523delCTT in CFTR, who carry two rare EHF alleles, were enriched for genes that alter protein glycosylation and trafficking, both mechanisms being pivotal for the effective targeting of fully functional p.Phe508del-CFTR to the apical membrane of epithelial cells. We conclude that EHF modifies the CF phenotype by altering capabilities of the epithelial cell to correctly process the folding and trafficking of mutant p.Phe508del-CFTR. European Journal of Human Genetics (2014) 22, 660–666; doi:10.1038/ejhg.2013.209; published online 9 October 2013 Keywords: cystic fibrosis modifier gene; c.1521_1523delCTT (p.Phe508del; F508del) in CFTR; association study; endophenotype; transcription factor; transcriptome INTRODUCTION Recently, Wright et al have described and replicated a significant The autosomal-recessively inherited monogenic disease cystic fibrosis association signal on a 11p13 intergenic region.14 We wanted to know (CF; OMIM #219700)1 is caused by two defective copies of the cystic whether we could reproduce this finding in our truly independent fibrosis transmembrane conductance regulator (CFTR)gene,2 which patient cohort of homozygotes for c.1521_1523delCTT in CFTR from encodes a chloride3 and bicarbonate4,5 channel localized in the apical the European CF Twin and Sibling Study, which differs from the North membrane of epithelial cells. The CFTR-transmitted basic defect can American CF Genetic Modifier Study by recruitment strategy, be used to diagnose the disease by the analysis of sweat glands,6,7 phenotype evaluation, choice of genetic markers and approach to nasal6,7 or intestinal epithelium.7 evaluate genetic data as outlined before.9 In addition, we have studied As CF is a rare disease affecting about 1:2000 newborns transcriptome data from rectal suction biopsies, as first, intestinal in the Caucasian population, sample sizes of several 10 000 epithelium expresses large amounts of CFTR15 and second, owing to individuals desirable for many genome-wide association studies the high turnover rate of epithelial cells in the intestine, these samples (GWAS)8 cannot be obtained for the rare disease CF. are less prone to secondary alterations by inflammatory processes in To preserve reasonable power to detect CF-modifying genes,9 comparison to pulmonary tissue.16 the European CF Twin and Sibling Study restricts the analysis to homozygotes of c.1521_1523delCTT in CFTR,studiesextreme PATIENTS AND METHODS 10,11 phenotypes in a case–reference setting and employs endopheno- Measurement of the CF basic defect 12,13 types rather than global clinical variables such as lung Assessment of the CF basic defect was carried out in vivo by nasal potential function. difference (NPD) measurement and ex vivo on rectal suction biopsies by 1Department of Pediatrics, Hannover Medical School, Hannover, Germany; 2Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research, Hannover, Germany; 3Institute for Pharmacy and Molecular Biotechnology, Ruperto-Carola University of Heidelberg, Heidelberg, Germany; 4German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany; 5Institute of Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany *Correspondence: Dr F Stanke, Department of Pediatrics, Hannover Medical School, Carl-Neuberg-Street 1, Hannover 30625, Germany. Tel: þ 49 511 532 6722; Fax: +49 511 532 6723; E-mail: [email protected] Received 26 April 2013; revised 26 July 2013; accepted 9 August 2013; published online 9 October 2013 EHF alters p.Phe508del-CFTR trafficking FStankeet al 661 intestinal current measurement (ICM). As outlined in detail elsewhere, Data evaluation and statistics secretagogues that activate or block ion channels, ion exchangers or compo- Genotyping data were evaluated using the software package FAMHAP (http:// nents of the cellular signal transduction pathways were applied by superfusion famhap.meb.uni-bonn.de/). Genetic data for the association study were of the lower nasal turbinate17 or to excised rectal suction biopsies mounted in evaluated using the FAMHAP software package,24 which allows family-based a micro-Ussing chamber.18 analysis 25,26 and accepts data evaluation in association with studies on We have used both techniques to discriminate between patients with and unrelated individuals as well as on affected sib pairs.24 Case–reference without residual chloride secretion. As ICM is an ex-vivo method applied to comparisons were carried out using 10 000 Monte–Carlo simulated data patient’s biopsies, the toxic compound DIDS (4,48-diisothiocyanostilbene- sets,24–26 whereby the analysis of more than one marker per locus is 2,28-disulfonic acid), which has been reported to block chloride channels other corrected for multiple testing by haplotype permutation.26 For this purpose, than CFTR, could be used to differentiate between CFTR-mediated residual the entire data set of cases and references is used to estimate haplotype chloride secretion and chloride secretion through alternative channels.19 Based frequencies.24 Haplotype, or, in cases of non-informative phase or haplotype on compounds used in NPD, contrasting phenotypes for the response to the uncertainty, weighted haplotype explanation lists are assigned to each individual applied secretagogues were defined whereby the work reported upon here is whereby the haplotype frequencies of the entire data set are taken into account focused on the response to amiloride, which blocks the epithelial sodium to compute the conditional likelihood weights.24 Permutation is done by channel ENaC. All ICM and NPD results obtained from twins and siblings, randomly assigning the affection status to the individuals in each replication which were used to characterize the role of EHF in CF, have been previously whereby the ratio of cases to controls is kept constant.24 described by Bronsveld et al.19,20 P-values for comparison of n-marker-haplotypes and all marker subsets derived thereof are computed as s/n,wheren is the number of permutation replicates and s is the number of permutation replicates leading to a test statistic higher than or equal to that of the real data.24 Reported P values are: Patient population Praw, referring to a computed P value of a single marker or marker The study population and the selection criteria for cases and references of the 9 combination and Pcorr, referring to the P value of the entire marker set that association study have been described in detail elsewhere. Briefly, genotyping is corrected for multiple testing of all genotyped markers. The adjustment for data from 101 CF families, 85 of which are a subgroup of the twin and sibling multiple testing properly accounts for LD within the Monte–Carlo simulation study panel of 466 twin and sibling pairs, were used for the association study.9 framework that evaluates the corrected significance minP, the smallest observed Sixteen unrelated homozygotes for c.1521_1523delCTT in CFTR with known raw P-value.25 The computational details of the minP principle have been basic defect and their parents were included into the analysis of the 25 9,21–23 described elsewhere. manifestation of the CF basic defect. For the endophenotype ‘response To allow a comparable assignment of weighted haplotype explanations in all to amiloride in NPD’, patients who showed a change of 27 mV or less upon subpopulations, the entire genotyping data of 101 CF families were provided as superfusion of the lower nasal turbinate with amiloride-containing solution a training set to FAMHAP for all case–reference comparisons.9 were defined as cases (13 unrelated patients).9 Patients who showed a change of 28 mV or more upon superfusion of the lower nasal turbinate with amiloride-containing solution were defined as references (17 unrelated Transcriptome
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