{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T19:47:44Z","timestamp":1792784864507,"version":"4.5.0"},"reference-count":75,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,11,23]],"date-time":"2021-11-23T00:00:00Z","timestamp":1637625600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,11,23]],"date-time":"2021-11-23T00:00:00Z","timestamp":1637625600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000060","name":"U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R37 AI045898"],"award-info":[{"award-number":["R37 AI045898"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006492","name":"Division of Intramural Research, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01 AI124355"],"award-info":[{"award-number":["R01 AI124355"]}],"id":[{"id":"10.13039\/100006492","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006492","name":"Division of Intramural Research, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["U19 AI070235"],"award-info":[{"award-number":["U19 AI070235"]}],"id":[{"id":"10.13039\/100006492","id-type":"DOI","asserted-by":"publisher"}]},{"name":"the Campaign Urging Research for Eosinophilic Disease (CURED); the Sunshine Charitable Foundation and its supporters, Denise A. Bunning and David G. Bunning"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Commun"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Eosinophilic esophagitis (EoE) is a chronic allergic inflammatory disease with a complex underlying genetic etiology. Herein, we conduct whole-exome sequencing of a multigeneration EoE pedigree (discovery set) and 61 additional multiplex families with EoE (replication set). A series of rare, heterozygous, missense variants are identified in the genes encoding the desmosome-associated proteins DSP and PPL in 21% of the multiplex families. Esophageal biopsies from patients with these variants retain dilated intercellular spaces and decrease DSP and PPL expression even during disease remission. These variants affect barrier integrity, cell motility and RhoGTPase activity in esophageal epithelial cells and have increased susceptibility to calpain-14\u2013mediated degradation. An acquired loss of esophageal DSP and PPL is present in non-familial EoE. Taken together, herein, we uncover a pathogenic role for desmosomal dysfunction in EoE, providing a deeper mechanistic understanding of tissue-specific allergic responses.<\/jats:p>","DOI":"10.1038\/s41467-021-26939-9","type":"journal-article","created":{"date-parts":[[2021,11,23]],"date-time":"2021-11-23T06:02:49Z","timestamp":1637647369000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":45,"title":["Desmoplakin and periplakin genetically and functionally contribute to eosinophilic esophagitis"],"prefix":"10.1038","volume":"12","author":[{"given":"Tetsuo","family":"Shoda","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth M.","family":"Kaufman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Wen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3855-299X","authenticated-orcid":false,"given":"Julie M.","family":"Caldwell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Garrett A.","family":"Osswald","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pathre","family":"Purnima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3624-5435","authenticated-orcid":false,"given":"Nives","family":"Zimmermann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0756-5974","authenticated-orcid":false,"given":"Margaret H.","family":"Collins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kira","family":"Rehn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather","family":"Foote","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael D.","family":"Eby","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenying","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6530-0387","authenticated-orcid":false,"given":"Netali","family":"Ben-Baruch Morgenstern","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adina Y.","family":"Ballaban","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeff E.","family":"Habel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3979-2220","authenticated-orcid":false,"given":"Leah C.","family":"Kottyan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. Pablo","family":"Abonia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent A.","family":"Mukkada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip E.","family":"Putnam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8702-9946","authenticated-orcid":false,"given":"Lisa J.","family":"Martin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9790-6332","authenticated-orcid":false,"given":"Marc E.","family":"Rothenberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,11,23]]},"reference":[{"key":"26939_CR1","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.jaci.2019.11.013","volume":"145","author":"LC Kottyan","year":"2020","unstructured":"Kottyan, L. C., Parameswaran, S., Weirauch, M. T., Rothenberg, M. E. & Martin, L. J. The genetic etiology of eosinophilic esophagitis. J. Allergy Clin. Immunol. 145, 9\u201315 (2020).","journal-title":"J. Allergy Clin. Immunol."},{"key":"26939_CR2","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1016\/j.cgh.2008.01.004","volume":"6","author":"MH Collins","year":"2008","unstructured":"Collins, M. H. et al. Clinical, pathologic, and molecular characterization of familial eosinophilic esophagitis compared with sporadic cases. Clin. Gastroenterol. Hepatol. 6, 621\u2013629 (2008).","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"26939_CR3","doi-asserted-by":"crossref","first-page":"1138","DOI":"10.1016\/j.jaci.2016.12.979","volume":"140","author":"K Allen-Brady","year":"2017","unstructured":"Allen-Brady, K. et al. Population-based familial aggregation of eosinophilic esophagitis suggests a genetic contribution. J. Allergy Clin. Immunol. 140, 1138\u20131143 (2017).","journal-title":"J. Allergy Clin. Immunol."},{"key":"26939_CR4","doi-asserted-by":"crossref","first-page":"1084","DOI":"10.1016\/j.jaci.2014.07.021","volume":"134","author":"ES Alexander","year":"2014","unstructured":"Alexander, E. S. et al. Twin and family studies reveal strong environmental and weaker genetic cues explaining heritability of eosinophilic esophagitis. J. Allergy Clin. Immunol. 134, 1084\u20131092.e1 (2014).","journal-title":"J. Allergy Clin. Immunol."},{"key":"26939_CR5","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1038\/ng.547","volume":"42","author":"ME Rothenberg","year":"2010","unstructured":"Rothenberg, M. E. et al. Common variants at 5q22 associate with pediatric eosinophilic esophagitis. Nat. Genet 42, 289\u2013291 (2010).","journal-title":"Nat. Genet"},{"key":"26939_CR6","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1038\/ng.3033","volume":"46","author":"LC Kottyan","year":"2014","unstructured":"Kottyan, L. C. et al. Genome-wide association analysis of eosinophilic esophagitis provides insight into the tissue specificity of this allergic disease. Nat. Genet 46, 895\u2013900 (2014).","journal-title":"Nat. Genet"},{"key":"26939_CR7","doi-asserted-by":"crossref","DOI":"10.1038\/ncomms6593","volume":"5","author":"PM Sleiman","year":"2014","unstructured":"Sleiman, P. M. et al. GWAS identifies four novel eosinophilic esophagitis loci. Nat. Commun. 5, 5593 (2014).","journal-title":"Nat. Commun."},{"key":"26939_CR8","doi-asserted-by":"crossref","first-page":"e86355","DOI":"10.1172\/jci.insight.86355","volume":"1","author":"BP Davis","year":"2016","unstructured":"Davis, B. P. et al. Eosinophilic esophagitis-linked calpain 14 is an IL-13-induced protease that mediates esophageal epithelial barrier impairment. JCI Insight 1, e86355 (2016).","journal-title":"JCI Insight"},{"key":"26939_CR9","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.jaci.2010.04.037","volume":"126","author":"JD Sherrill","year":"2010","unstructured":"Sherrill, J. D. et al. Variants of thymic stromal lymphopoietin and its receptor associate with eosinophilic esophagitis. J. Allergy Clin. Immunol. 126, 160\u20135.e3 (2010).","journal-title":"J. Allergy Clin. Immunol."},{"key":"26939_CR10","doi-asserted-by":"publisher","first-page":"469","DOI":"10.1038\/nature13127","volume":"508","author":"DG MacArthur","year":"2014","unstructured":"MacArthur, D. G. et al. Guidelines for investigating causality of sequence variants in human disease. Nature 508, 469\u2013476 (2014).","journal-title":"Nature"},{"key":"26939_CR11","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1038\/jid.2013.498","volume":"134","author":"JE Bouameur","year":"2014","unstructured":"Bouameur, J. E., Favre, B. & Borradori, L. Plakins, a versatile family of cytolinkers: roles in skin integrity and in human diseases. J. Invest Dermatol 134, 885\u2013894 (2014).","journal-title":"J. Invest Dermatol"},{"key":"26939_CR12","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1007\/s00441-015-2136-5","volume":"360","author":"JA Broussard","year":"2015","unstructured":"Broussard, J. A., Getsios, S. & Green, K. J. Desmosome regulation and signaling in disease. Cell Tissue Res. 360, 501\u2013512 (2015).","journal-title":"Cell Tissue Res."},{"key":"26939_CR13","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1146\/annurev-pathol-020117-044030","volume":"13","author":"NA Najor","year":"2018","unstructured":"Najor, N. A. Desmosomes in human disease. Annu Rev. Pathol. 13, 51\u201370 (2018).","journal-title":"Annu Rev. Pathol."},{"key":"26939_CR14","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1038\/nature19057","volume":"536","author":"M Lek","year":"2016","unstructured":"Lek, M. et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature 536, 285\u2013291 (2016).","journal-title":"Nature"},{"key":"26939_CR15","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1038\/s41586-018-0579-z","volume":"562","author":"C Bycroft","year":"2018","unstructured":"Bycroft, C. et al. The UK Biobank resource with deep phenotyping and genomic data. Nature 562, 203\u2013209 (2018).","journal-title":"Nature"},{"key":"26939_CR16","first-page":"1","volume":"30","author":"MH Collins","year":"2017","unstructured":"Collins, M. H. et al. Newly developed and validated eosinophilic esophagitis histology scoring system and evidence that it outperforms peak eosinophil count for disease diagnosis and monitoring. Dis. Esophagus 30, 1\u20138 (2017).","journal-title":"Dis. Esophagus"},{"key":"26939_CR17","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1053\/j.gastro.2013.08.046","volume":"145","author":"T Wen","year":"2013","unstructured":"Wen, T. et al. Molecular diagnosis of eosinophilic esophagitis by gene expression profiling. Gastroenterology 145, 1289\u20131299 (2013).","journal-title":"Gastroenterology"},{"key":"26939_CR18","doi-asserted-by":"crossref","first-page":"2014","DOI":"10.1172\/JCI125917","volume":"129","author":"T Wen","year":"2019","unstructured":"Wen, T. et al. Single-cell RNA sequencing identifies inflammatory tissue T cells in eosinophilic esophagitis. J. Clin. Invest 129, 2014\u20132028 (2019).","journal-title":"J. Clin. Invest"},{"key":"26939_CR19","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1111\/imr.12546","volume":"278","author":"H Han","year":"2017","unstructured":"Han, H., Roan, F. & Ziegler, S. F. The atopic march: current insights into skin barrier dysfunction and epithelial cell-derived cytokines. Immunol. Rev. 278, 116\u2013130 (2017).","journal-title":"Immunol. Rev."},{"key":"26939_CR20","doi-asserted-by":"crossref","unstructured":"Ng, R. et al. Patient mutations linked to arrhythmogenic cardiomyopathy enhance calpain-mediated desmoplakin degradation. JCI Insight 5, e128643 (2019).","DOI":"10.1172\/jci.insight.128643"},{"key":"26939_CR21","doi-asserted-by":"crossref","first-page":"1268","DOI":"10.1016\/j.jaci.2015.05.002","volume":"136","author":"MA McAleer","year":"2015","unstructured":"McAleer, M. A. et al. Severe dermatitis, multiple allergies, and metabolic wasting syndrome caused by a novel mutation in the N-terminal plakin domain of desmoplakin. J. Allergy Clin. Immunol. 136, 1268\u20131276 (2015).","journal-title":"J. Allergy Clin. Immunol."},{"key":"26939_CR22","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1242\/jcs.097923","volume":"126","author":"J McCormack","year":"2013","unstructured":"McCormack, J., Welsh, N. J. & Braga, V. M. Cycling around cell\u2013cell adhesion with Rho GTPase regulators. J. Cell Sci. 126, 379\u2013391 (2013).","journal-title":"J. Cell Sci."},{"key":"26939_CR23","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1016\/j.jid.2018.11.032","volume":"139","author":"JL Bendrick","year":"2019","unstructured":"Bendrick, J. L., Eldredge, L. A., Williams, E. I., Haight, N. B. & Dubash, A. D. Desmoplakin harnesses Rho GTPase and p38 mitogen-activated protein kinase signaling to coordinate cellular migration. J. Invest Dermatol. 139, 1227\u20131236 (2019).","journal-title":"J. Invest Dermatol."},{"key":"26939_CR24","doi-asserted-by":"crossref","first-page":"2317","DOI":"10.1016\/j.jacc.2010.12.036","volume":"57","author":"JD Kapplinger","year":"2011","unstructured":"Kapplinger, J. D. et al. Distinguishing arrhythmogenic right ventricular cardiomyopathy\/dysplasia-associated mutations from background genetic noise. J. Am. Coll. Cardiol. 57, 2317\u20132327 (2011).","journal-title":"J. Am. Coll. Cardiol."},{"key":"26939_CR25","doi-asserted-by":"crossref","first-page":"1114","DOI":"10.1111\/bjd.17388","volume":"180","author":"T Maruthappu","year":"2019","unstructured":"Maruthappu, T. et al. Loss-of-function desmoplakin I and II mutations underlie dominant arrhythmogenic cardiomyopathy with a hair and skin phenotype. Br. J. Dermatol 180, 1114\u20131122 (2019).","journal-title":"Br. J. Dermatol"},{"key":"26939_CR26","doi-asserted-by":"crossref","first-page":"1838","DOI":"10.1093\/europace\/euu128","volume":"16","author":"JM L\u00f3pez-Ayala","year":"2014","unstructured":"L\u00f3pez-Ayala, J. M. et al. Desmoplakin truncations and arrhythmogenic left ventricular cardiomyopathy: characterizing a phenotype. Europace 16, 1838\u20131846 (2014).","journal-title":"Europace"},{"key":"26939_CR27","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1093\/europace\/euq104","volume":"12","author":"V Fressart","year":"2010","unstructured":"Fressart, V. et al. Desmosomal gene analysis in arrhythmogenic right ventricular dysplasia\/cardiomyopathy: spectrum of mutations and clinical impact in practice. Europace 12, 861\u2013868 (2010).","journal-title":"Europace"},{"key":"26939_CR28","doi-asserted-by":"crossref","first-page":"1762","DOI":"10.1016\/j.jaci.2016.09.027","volume":"139","author":"VA Litosh","year":"2017","unstructured":"Litosh, V. A. et al. Calpain-14 and its association with eosinophilic esophagitis. J. Allergy Clin. Immunol. 139, 1762\u20131771.e7 (2017).","journal-title":"J. Allergy Clin. Immunol."},{"key":"26939_CR29","doi-asserted-by":"crossref","first-page":"854","DOI":"10.1038\/nrd.2016.212","volume":"15","author":"Y Ono","year":"2016","unstructured":"Ono, Y., Saido, T. C. & Sorimachi, H. Calpain research for drug discovery: challenges and potential. Nat. Rev. Drug Disco. 15, 854\u2013876 (2016).","journal-title":"Nat. Rev. Drug Disco."},{"key":"26939_CR30","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1111\/all.12570","volume":"70","author":"D Simon","year":"2015","unstructured":"Simon, D., Radonjic-Hosli, S., Straumann, A., Yousefi, S. & Simon, H. U. Active eosinophilic esophagitis is characterized by epithelial barrier defects and eosinophil extracellular trap formation. Allergy 70, 443\u2013452 (2015).","journal-title":"Allergy"},{"key":"26939_CR31","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1016\/j.jaci.2016.11.042","volume":"140","author":"M Rochman","year":"2017","unstructured":"Rochman, M. et al. Profound loss of esophageal tissue differentiation in patients with eosinophilic esophagitis. J. Allergy Clin. Immunol. 140, 738\u2013749 e3 (2017).","journal-title":"J. Allergy Clin. Immunol."},{"key":"26939_CR32","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1534\/g3.118.200901","volume":"9","author":"DE Miller","year":"2019","unstructured":"Miller, D. E. et al. Genetic, inflammatory, and epithelial cell differentiation factors control expression of human Calpain-14. G3 (Bethesda) 9, 729\u2013736 (2019).","journal-title":"G3 (Bethesda)"},{"key":"26939_CR33","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1038\/mi.2013.90","volume":"7","author":"JD Sherrill","year":"2014","unstructured":"Sherrill, J. D. et al. Desmoglein-1 regulates esophageal epithelial barrier function and immune responses in eosinophilic esophagitis. Mucosal Immunol. 7, 718\u2013729 (2014).","journal-title":"Mucosal Immunol."},{"key":"26939_CR34","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1136\/jclinpath-2014-202586","volume":"68","author":"KE Capocelli","year":"2015","unstructured":"Capocelli, K. E. et al. Ultrastructural features of eosinophilic oesophagitis: impact of treatment on desmosomes. J. Clin. Pathol. 68, 51\u201356 (2015).","journal-title":"J. Clin. Pathol."},{"key":"26939_CR35","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.jdermsci.2014.02.005","volume":"74","author":"A Ishida-Yamamoto","year":"2014","unstructured":"Ishida-Yamamoto, A. & Igawa, S. Genetic skin diseases related to desmosomes and corneodesmosomes. J. Dermatol Sci. 74, 99\u2013105 (2014).","journal-title":"J. Dermatol Sci."},{"key":"26939_CR36","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1084\/jem.20172306","volume":"215","author":"JJ Lyons","year":"2018","unstructured":"Lyons, J. J. & Milner, J. D. Primary atopic disorders. J. Exp. Med. 215, 1009\u20131022 (2018).","journal-title":"J. Exp. Med."},{"key":"26939_CR37","doi-asserted-by":"crossref","first-page":"1244","DOI":"10.1038\/ng.2739","volume":"45","author":"L Samuelov","year":"2013","unstructured":"Samuelov, L. et al. Desmoglein 1 deficiency results in severe dermatitis, multiple allergies and metabolic wasting. Nat. Genet 45, 1244\u20131248 (2013).","journal-title":"Nat. Genet"},{"key":"26939_CR38","doi-asserted-by":"crossref","first-page":"1599","DOI":"10.1083\/jcb.200706187","volume":"179","author":"LM Sevilla","year":"2007","unstructured":"Sevilla, L. M. et al. Mice deficient in involucrin, envoplakin, and periplakin have a defective epidermal barrier. J. Cell Biol. 179, 1599\u20131612 (2007).","journal-title":"J. Cell Biol."},{"key":"26939_CR39","doi-asserted-by":"crossref","first-page":"109","DOI":"10.3109\/15419061.2014.906533","volume":"21","author":"DM Patel","year":"2014","unstructured":"Patel, D. M. & Green, K. J. Desmosomes in the heart: a review of clinical and mechanistic analyses. Cell Commun. Adhes. 21, 109\u2013128 (2014).","journal-title":"Cell Commun. Adhes."},{"key":"26939_CR40","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1038\/jid.2009.357","volume":"130","author":"MG Mahoney","year":"2010","unstructured":"Mahoney, M. G. et al. Compound heterozygous desmoplakin mutations result in a phenotype with a combination of myocardial, skin, hair, and enamel abnormalities. J. Invest Dermatol 130, 968\u2013978 (2010).","journal-title":"J. Invest Dermatol"},{"key":"26939_CR41","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1038\/s41576-019-0200-9","volume":"21","author":"I Hekselman","year":"2020","unstructured":"Hekselman, I. & Yeger-Lotem, E. Mechanisms of tissue and cell-type specificity in heritable traits and diseases. Nat. Rev. Genet 21, 137\u2013150 (2020).","journal-title":"Nat. Rev. Genet"},{"key":"26939_CR42","doi-asserted-by":"crossref","first-page":"1022","DOI":"10.1053\/j.gastro.2018.07.009","volume":"155","author":"ES Dellon","year":"2018","unstructured":"Dellon, E. S. et al. Updated international consensus diagnostic criteria for eosinophilic esophagitis: proceedings of the AGREE conference. Gastroenterology 155, 1022\u20131033 e10 (2018).","journal-title":"Gastroenterology"},{"key":"26939_CR43","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1101\/gr.107524.110","volume":"20","author":"A McKenna","year":"2010","unstructured":"McKenna, A. et al. The genome analysis toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 20, 1297\u20131303 (2010).","journal-title":"Genome Res."},{"key":"26939_CR44","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1038\/ng.806","volume":"43","author":"MA DePristo","year":"2011","unstructured":"DePristo, M. A. et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat. Genet 43, 491\u2013498 (2011).","journal-title":"Nat. Genet"},{"key":"26939_CR45","doi-asserted-by":"crossref","first-page":"11.10.1","DOI":"10.1002\/0471250953.bi1110s43","volume":"43","author":"GA Van der Auwera","year":"2013","unstructured":"Van der Auwera, G. A. et al. From FastQ data to high confidence variant calls: the genome analysis toolkit best practices pipeline. Curr. Protoc. Bioinforma. 43, 11.10.1\u201311.10.33 (2013).","journal-title":"Curr. Protoc. Bioinforma."},{"key":"26939_CR46","doi-asserted-by":"crossref","first-page":"16","DOI":"10.3389\/fgene.2014.00016","volume":"5","author":"ZH Patel","year":"2014","unstructured":"Patel, Z. H. et al. The struggle to find reliable results in exome sequencing data: filtering out Mendelian errors. Front Genet 5, 16 (2014).","journal-title":"Front Genet"},{"key":"26939_CR47","doi-asserted-by":"crossref","first-page":"e164","DOI":"10.1093\/nar\/gkq603","volume":"38","author":"K Wang","year":"2010","unstructured":"Wang, K., Li, M. & Hakonarson, H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 38, e164 (2010).","journal-title":"Nucleic Acids Res"},{"key":"26939_CR48","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/nature11632","volume":"491","author":"GR Abecasis","year":"2012","unstructured":"Abecasis, G. R. et al. An integrated map of genetic variation from 1,092 human genomes. Nature 491, 56\u201365 (2012).","journal-title":"Nature"},{"key":"26939_CR49","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1126\/science.1219240","volume":"337","author":"JA Tennessen","year":"2012","unstructured":"Tennessen, J. A. et al. Evolution and functional impact of rare coding variation from deep sequencing of human exomes. Science 337, 64\u201369 (2012).","journal-title":"Science"},{"key":"26939_CR50","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1002\/humu.21517","volume":"32","author":"X Liu","year":"2011","unstructured":"Liu, X., Jian, X. & Boerwinkle, E. dbNSFP: a lightweight database of human nonsynonymous SNPs and their functional predictions. Hum. Mutat. 32, 894\u2013899 (2011).","journal-title":"Hum. Mutat."},{"key":"26939_CR51","doi-asserted-by":"crossref","first-page":"E2393","DOI":"10.1002\/humu.22376","volume":"34","author":"X Liu","year":"2013","unstructured":"Liu, X., Jian, X. & Boerwinkle, E. dbNSFP v2.0: a database of human non-synonymous SNVs and their functional predictions and annotations. Hum. Mutat. 34, E2393\u2013E2402 (2013).","journal-title":"Hum. Mutat."},{"key":"26939_CR52","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1002\/humu.22932","volume":"37","author":"X Liu","year":"2016","unstructured":"Liu, X., Wu, C., Li, C. & Boerwinkle, E. dbNSFP v3.0: a one-stop database of functional predictions and annotations for human nonsynonymous and splice-site SNVs. Hum. Mutat. 37, 235\u2013241 (2016).","journal-title":"Hum. Mutat."},{"key":"26939_CR53","doi-asserted-by":"crossref","first-page":"3812","DOI":"10.1093\/nar\/gkg509","volume":"31","author":"PC Ng","year":"2003","unstructured":"Ng, P. C. & Henikoff, S. SIFT: predicting amino acid changes that affect protein function. Nucleic Acids Res. 31, 3812\u20133814 (2003).","journal-title":"Nucleic Acids Res."},{"key":"26939_CR54","doi-asserted-by":"crossref","first-page":"1553","DOI":"10.1101\/gr.092619.109","volume":"19","author":"S Chun","year":"2009","unstructured":"Chun, S. & Fay, J. C. Identification of deleterious mutations within three human genomes. Genome Res. 19, 1553\u20131561 (2009).","journal-title":"Genome Res."},{"key":"26939_CR55","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1038\/nmeth0410-248","volume":"7","author":"IA Adzhubei","year":"2010","unstructured":"Adzhubei, I. A. et al. A method and server for predicting damaging missense mutations. Nat. Methods 7, 248\u2013249 (2010).","journal-title":"Nat. Methods"},{"key":"26939_CR56","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1038\/nmeth0810-575","volume":"7","author":"JM Schwarz","year":"2010","unstructured":"Schwarz, J. M., Rodelsperger, C., Schuelke, M. & Seelow, D. MutationTaster evaluates disease-causing potential of sequence alterations. Nat. Methods 7, 575\u2013576 (2010).","journal-title":"Nat. Methods"},{"key":"26939_CR57","doi-asserted-by":"crossref","first-page":"e118","DOI":"10.1093\/nar\/gkr407","volume":"39","author":"B Reva","year":"2011","unstructured":"Reva, B., Antipin, Y. & Sander, C. Predicting the functional impact of protein mutations: application to cancer genomics. Nucleic Acids Res. 39, e118 (2011).","journal-title":"Nucleic Acids Res."},{"key":"26939_CR58","doi-asserted-by":"crossref","first-page":"1504","DOI":"10.1093\/bioinformatics\/btt182","volume":"29","author":"HA Shihab","year":"2013","unstructured":"Shihab, H. A., Gough, J., Cooper, D. N., Day, I. N. & Gaunt, T. R. Predicting the functional consequences of cancer-associated amino acid substitutions. Bioinformatics 29, 1504\u20131510 (2013).","journal-title":"Bioinformatics"},{"key":"26939_CR59","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1038\/ng.2892","volume":"46","author":"M Kircher","year":"2014","unstructured":"Kircher, M. et al. A general framework for estimating the relative pathogenicity of human genetic variants. Nat. Genet 46, 310\u2013315 (2014).","journal-title":"Nat. Genet"},{"key":"26939_CR60","doi-asserted-by":"crossref","first-page":"2125","DOI":"10.1093\/hmg\/ddu733","volume":"24","author":"C Dong","year":"2015","unstructured":"Dong, C. et al. Comparison and integration of deleteriousness prediction methods for nonsynonymous SNVs in whole exome sequencing studies. Hum. Mol. Genet 24, 2125\u20132137 (2015).","journal-title":"Hum. Mol. Genet"},{"key":"26939_CR61","doi-asserted-by":"crossref","first-page":"e104452","DOI":"10.1371\/journal.pone.0104452","volume":"9","author":"Q Li","year":"2014","unstructured":"Li, Q. et al. Gene-specific function prediction for non-synonymous mutations in monogenic diabetes genes. PLoS ONE 9, e104452 (2014).","journal-title":"PLoS ONE"},{"key":"26939_CR62","doi-asserted-by":"crossref","first-page":"D670","DOI":"10.1093\/nar\/gku1177","volume":"43","author":"KR Rosenbloom","year":"2015","unstructured":"Rosenbloom, K. R. et al. The UCSC Genome Browser database: 2015 update. Nucleic Acids Res 43, D670\u2013D681 (2015).","journal-title":"Nucleic Acids Res"},{"key":"26939_CR63","doi-asserted-by":"crossref","first-page":"i54","DOI":"10.1093\/bioinformatics\/btp190","volume":"25","author":"M Garber","year":"2009","unstructured":"Garber, M. et al. Identifying novel constrained elements by exploiting biased substitution patterns. Bioinformatics 25, i54\u2013i62 (2009).","journal-title":"Bioinformatics"},{"key":"26939_CR64","doi-asserted-by":"crossref","first-page":"e1001025","DOI":"10.1371\/journal.pcbi.1001025","volume":"6","author":"EV Davydov","year":"2010","unstructured":"Davydov, E. V. et al. Identifying a high fraction of the human genome to be under selective constraint using GERP++. PLoS Comput. Biol. 6, e1001025 (2010).","journal-title":"PLoS Comput. Biol."},{"key":"26939_CR65","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1101\/gr.097857.109","volume":"20","author":"KS Pollard","year":"2010","unstructured":"Pollard, K. S., Hubisz, M. J., Rosenbloom, K. R. & Siepel, A. Detection of nonneutral substitution rates on mammalian phylogenies. Genome Res. 20, 110\u2013121 (2010).","journal-title":"Genome Res."},{"key":"26939_CR66","doi-asserted-by":"crossref","first-page":"1690","DOI":"10.1016\/j.jaci.2017.09.046","volume":"141","author":"LJ Martin","year":"2018","unstructured":"Martin, L. J. et al. Eosinophilic esophagitis (EoE) genetic susceptibility is mediated by synergistic interactions between EoE-specific and general atopic disease loci. J. Allergy Clin. Immunol. 141, 1690\u20131698 (2018).","journal-title":"J. Allergy Clin. Immunol."},{"key":"26939_CR67","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1016\/S2468-1253(18)30096-7","volume":"3","author":"T Shoda","year":"2018","unstructured":"Shoda, T. et al. Eosinophilic oesophagitis endotype classification by molecular, clinical, and histopathological analyses: a cross-sectional study. Lancet Gastroenterol. Hepatol. 3, 477\u2013488 (2018).","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"26939_CR68","doi-asserted-by":"crossref","first-page":"1519","DOI":"10.1016\/j.jaci.2015.03.004","volume":"135","author":"LJ Martin","year":"2015","unstructured":"Martin, L. J. et al. Pediatric eosinophilic esophagitis symptom scores (PEESS v2.0) identify histologic and molecular correlates of the key clinical features of disease. J. Allergy Clin. Immunol. 135, 1519\u201328.e8 (2015).","journal-title":"J. Allergy Clin. Immunol."},{"key":"26939_CR69","doi-asserted-by":"crossref","unstructured":"Rochman, M., Travers, J., Abonia, J. P., Caldwell, J. M. & Rothenberg, M. E. Synaptopodin is upregulated by IL-13 in eosinophilic esophagitis and regulates esophageal epithelial cell motility and barrier integrity. JCI Insight 2, e96789 (2017).","DOI":"10.1172\/jci.insight.96789"},{"key":"26939_CR70","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1172\/JCI26679","volume":"116","author":"C Blanchard","year":"2006","unstructured":"Blanchard, C. et al. Eotaxin-3 and a uniquely conserved gene-expression profile in eosinophilic esophagitis. J. Clin. Invest 116, 536\u2013547 (2006).","journal-title":"J. Clin. Invest"},{"key":"26939_CR71","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1038\/nbt.4096","volume":"36","author":"A Butler","year":"2018","unstructured":"Butler, A., Hoffman, P., Smibert, P., Papalexi, E. & Satija, R. Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat. Biotechnol. 36, 411\u2013420 (2018).","journal-title":"Nat. Biotechnol."},{"key":"26939_CR72","doi-asserted-by":"crossref","first-page":"e0179383","DOI":"10.1371\/journal.pone.0179383","volume":"12","author":"B Jakic","year":"2017","unstructured":"Jakic, B., Buszko, M., Cappellano, G. & Wick, G. Elevated sodium leads to the increased expression of HSP60 and induces apoptosis in HUVECs. PLoS ONE 12, e0179383 (2017).","journal-title":"PLoS ONE"},{"key":"26939_CR73","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1038\/nbt.3437","volume":"34","author":"JG Doench","year":"2016","unstructured":"Doench, J. G. et al. Optimized sgRNA design to maximize activity and minimize off-target effects of CRISPR-Cas9. Nat. Biotechnol. 34, 184\u2013191 (2016).","journal-title":"Nat. Biotechnol."},{"key":"26939_CR74","doi-asserted-by":"crossref","DOI":"10.1186\/s13059-016-1012-2","volume":"17","author":"M Haeussler","year":"2016","unstructured":"Haeussler, M. et al. Evaluation of off-target and on-target scoring algorithms and integration into the guide RNA selection tool CRISPOR. Genome Biol. 17, 148 (2016).","journal-title":"Genome Biol."},{"key":"26939_CR75","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1111\/jnc.12629","volume":"130","author":"VH Knaryan","year":"2014","unstructured":"Knaryan, V. H. et al. SNJ-1945, a calpain inhibitor, protects SH-SY5Y cells against MPP(+) and rotenone. J. Neurochem 130, 280\u2013290 (2014).","journal-title":"J. Neurochem"}],"container-title":["Nature Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41467-021-26939-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-021-26939-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-021-26939-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,15]],"date-time":"2023-01-15T20:58:35Z","timestamp":1673816315000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41467-021-26939-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,23]]},"references-count":75,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["26939"],"URL":"https:\/\/doi.org\/10.1038\/s41467-021-26939-9","relation":{},"ISSN":["2041-1723"],"issn-type":[{"value":"2041-1723","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,23]]},"assertion":[{"value":"29 September 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 October 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 November 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare competing financial interests. M.E.R. is a consultant for Pulm One, Spoon Guru, Celgene, Shire, Astra Zeneca, GlaxoSmithKline, Allakos, Adare, Regeneron, and Novartis and has an equity interest in Pulm One, ClostaBio, and Spoon Guru, and royalties from reslizumab (Teva Pharmaceuticals). M.E.R. is an inventor of patents owned by Cincinnati Children\u2019s Hospital Medical Center. M.H.C. is a consultant for Shire, Regeneron, Receptos\/Celgene, GlaxoSmithKline, Esocap, Astra Zeneca, Arena, and Allakos and has received research funding from Shire, Regeneron and Receptos\/Celgene. V.A.M. is a consultant for Shire and has received research funding from Shire. T.S. has received research support from JSPS Overseas Research Fellowships and is a co-inventor of patents owned by Cincinnati Children\u2019s Hospital Medical Center. All other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"6795"}}