{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T16:29:50Z","timestamp":1780504190172,"version":"3.54.1"},"reference-count":36,"publisher":"The Company of Biologists","issue":"4","license":[{"start":{"date-parts":[[2020,9,3]],"date-time":"2020-09-03T00:00:00Z","timestamp":1599091200000},"content-version":"vor","delay-in-days":521,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100000268","name":"Biotechnology and Biological Sciences Research Council","doi-asserted-by":"publisher","award":["BB\/J004316\/1"],"award-info":[{"award-number":["BB\/J004316\/1"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010949","name":"College of Medicine and Veterinary Medicine, University of Edinburgh","doi-asserted-by":"publisher","award":["D33802"],"award-info":[{"award-number":["D33802"]}],"id":[{"id":"10.13039\/100010949","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001711","name":"Swiss National Science Foundation","doi-asserted-by":"publisher","award":["310030_156961"],"award-info":[{"award-number":["310030_156961"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001711","name":"Swiss National Science Foundation","doi-asserted-by":"publisher","award":["310030A_176256"],"award-info":[{"award-number":["310030A_176256"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000848","name":"University of Edinburgh","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000848","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,4,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:p>Patients with mutations in the ectodysplasin receptor signalling pathway genes \u2013 the X-linked ligand ectodysplasin-A (EDA), the receptor EDAR or the receptor adapter EDARADD \u2013 have hypohidrotic ectodermal dysplasia (HED). In addition to having impaired development of teeth, hair, eccrine sweat glands, and salivary and mammary glands, HED patients have ear, nose and throat disease. The mouse strains Tabby (EdaTa) and downless (Edardl-J\/dl-J) have rhinitis and otitis media due to loss of submucosal glands in the upper airway. We report that prenatal correction of EDAR signalling in EdaTa mice with the agonist anti-EDAR antibody rescues the auditory-tube submucosal glands and prevents otitis media, rhinitis and nasopharyngitis. The sparse- and wavy-haired (swh) rat strain carries a mutation in the Edaradd gene and has similar cutaneous HED phenotypes to mouse models. We report that auditory-tube submucosal glands are smaller in the homozygous mutant Edaraddswh\/swh than those in unaffected heterozygous Edaraddswh\/+ rats, and that this predisposes them to otitis media. Furthermore, the pathogenesis of otitis media in the rat HED model differs from that in mice, as otitis media is the primary pathology, and rhinitis is a later-onset phenotype. These findings in rodent HED models imply that hypomorphic as well as null mutations in EDAR signalling pathway genes may predispose to otitis media in humans. In addition, this work suggests that the recent successful prenatal treatment of X-linked HED (XLHED) in humans may also prevent ear, nose and throat disease, and provides diagnostic criteria that distinguish HED-associated otitis media from chronic otitis media with effusion, which is common in children.<\/jats:p>","DOI":"10.1242\/dmm.037804","type":"journal-article","created":{"date-parts":[[2019,4,25]],"date-time":"2019-04-25T13:05:20Z","timestamp":1556197520000},"source":"Crossref","is-referenced-by-count":16,"title":["Role of ectodysplasin signalling in middle ear and nasal pathology in rat and mouse models of hypohidrotic ectodermal dysplasia"],"prefix":"10.1242","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9582-1228","authenticated-orcid":false,"given":"Jorge","family":"del-Pozo","sequence":"first","affiliation":[{"name":"The Royal (Dick) School of Veterinary Studies, University of Edinburgh 1 Veterinary Pathology , , Edinburgh EH25 9RG , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil","family":"MacIntyre","sequence":"additional","affiliation":[{"name":"The Royal (Dick) School of Veterinary Studies, University of Edinburgh 1 Veterinary Pathology , , Edinburgh EH25 9RG , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali","family":"Azar","sequence":"additional","affiliation":[{"name":"Roslin Institute and The Royal (Dick) School of Veterinary Studies, University of Edinburgh 2 Developmental Biology Division , , Edinburgh EH25 9RG , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0452-4480","authenticated-orcid":false,"given":"Denis","family":"Headon","sequence":"additional","affiliation":[{"name":"Roslin Institute and The Royal (Dick) School of Veterinary Studies, University of Edinburgh 2 Developmental Biology Division , , Edinburgh EH25 9RG , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0677-9409","authenticated-orcid":false,"given":"Pascal","family":"Schneider","sequence":"additional","affiliation":[{"name":"University of Lausanne 3 Department of Biochemistry , , Boveresses 155, CH-1066 \u2008 Epalinges , Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5968-0176","authenticated-orcid":false,"given":"Michael","family":"Cheeseman","sequence":"additional","affiliation":[{"name":"Roslin Institute and The Royal (Dick) School of Veterinary Studies, University of Edinburgh 2 Developmental Biology Division , , Edinburgh EH25 9RG , UK"},{"name":"Centre for Comparative Pathology & Division of Pathology, University of Edinburgh, Institute of Genetics & Molecular Medicine 4 , Crewe Road, Edinburgh EH4 2XR , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2019,4,25]]},"reference":[{"key":"2024061302171950200_DMM037804C1","doi-asserted-by":"publisher","first-page":"3564","DOI":"10.1093\/hmg\/ddw202","article-title":"Ectodysplasin signalling deficiency in mouse models of Hypohidrotic Ectodermal Dysplasia leads to middle ear and nasal pathology","volume":"25","author":"Azar","year":"2016","journal-title":"Hum. Mol. Genet."},{"key":"2024061302171950200_DMM037804C2","doi-asserted-by":"crossref","DOI":"10.1007\/978-0-387-39258-5","volume-title":"Micro-Tomographic Atlas of the Mouse Skeleton","author":"Bab","year":"2007"},{"key":"2024061302171950200_DMM037804C3","doi-asserted-by":"publisher","first-page":"16878","DOI":"10.1038\/s41598-017-17204-5","article-title":"QuPath: open source software for digital pathology image analysis","volume":"7","author":"Bankhead","year":"2017","journal-title":"Sci. Rep."},{"key":"2024061302171950200_DMM037804C4","doi-asserted-by":"publisher","first-page":"501","DOI":"10.1242\/dmm.019646","article-title":"Increased susceptibility to otitis media in a Splunc1-deficient mouse model","volume":"8","author":"Bartlett","year":"2015","journal-title":"Dis. Model. Mech."},{"key":"2024061302171950200_DMM037804C5","doi-asserted-by":"publisher","first-page":"1099","DOI":"10.1017\/S002221510012540X","article-title":"Eustachian tube submucosal glands in normal and pathological temporal bones","volume":"107","author":"Berger","year":"1993","journal-title":"J. Laryngol. Otol."},{"key":"2024061302171950200_DMM037804C6","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1242\/dmm.029983","article-title":"Understanding the aetiology and resolution of chronic otitis media from animal and human studies","volume":"10","author":"Bhutta","year":"2017","journal-title":"Dis. Model. Mech."},{"key":"2024061302171950200_DMM037804C7","doi-asserted-by":"publisher","first-page":"1801","DOI":"10.1016\/j.ijporl.2013.09.004","article-title":"Ear nose throat manifestations in hypoidrotic ectodermal dysplasia","volume":"77","author":"Callea","year":"2013","journal-title":"Int. J. Pediatr. Otorhinolaryngol."},{"key":"2024061302171950200_DMM037804C8","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1016\/j.jcpa.2015.08.009","article-title":"A review of the comparative anatomy, histology, physiology and pathology of the nasal cavity of rats, mice, dogs and non-human primates. Relevance to inhalation toxicology and human health risk assessment","volume":"153","author":"Chamanza","year":"2015","journal-title":"J. Comp. Pathol."},{"key":"2024061302171950200_DMM037804C9","doi-asserted-by":"publisher","first-page":"e7591","DOI":"10.1371\/journal.pone.0007591","article-title":"Enhanced Edar signalling has pleiotropic effects on craniofacial and cutaneous glands","volume":"4","author":"Chang","year":"2009","journal-title":"PLoS. ONE"},{"key":"2024061302171950200_DMM037804C10","doi-asserted-by":"publisher","first-page":"dmm038315","DOI":"10.1242\/dmm.038315","article-title":"Chronic otitis media is initiated by a bulla cavitation defect in the FBXO11 mouse model","volume":"12","author":"del-Pozo","year":"2019","journal-title":"Dis. Model. Mech."},{"key":"2024061302171950200_DMM037804C11","first-page":"1","article-title":"The glandular aspects of the tabby syndrome in the mouse","volume":"25","author":"Gr\u00fcneberg","year":"1971","journal-title":"J. Embryol. Exp. Morphol."},{"key":"2024061302171950200_DMM037804C12","doi-asserted-by":"publisher","first-page":"651","DOI":"10.1111\/age.12729","article-title":"A frameshift variant in the EDA gene in Dachshunds with X-linked hypohidrotic ectodermal dysplasia","volume":"49","author":"Hadji Rasouliha","year":"2018","journal-title":"Anim. Genet."},{"key":"2024061302171950200_DMM037804C13","doi-asserted-by":"publisher","first-page":"2059","DOI":"10.1002\/ajmg.a.36582","article-title":"A novel mutation in the EDAR gene causes severe autosomal recessive hypohidrotic ectodermal dysplasia","volume":"164A","author":"Henningsen","year":"2014","journal-title":"Am. J. Med. Genet. A."},{"key":"2024061302171950200_DMM037804C14","doi-asserted-by":"publisher","first-page":"322","DOI":"10.1002\/ar.a.10045","article-title":"Ectodysplasin receptor-mediated signaling is essential for embryonic submandibular salivary gland development","volume":"271","author":"Jaskoll","year":"2003","journal-title":"Anat. Rec. A Discov. Mol. Cell Evol. Biol."},{"key":"2024061302171950200_DMM037804C15","doi-asserted-by":"publisher","first-page":"578","DOI":"10.1111\/j.1365-2052.2011.02192.x","article-title":"Exonization of a LINE1 fragment implicated in X-linked hypohidrotic ectodermal dysplasia in cattle","volume":"42","author":"Karlskov-Mortensen","year":"2011","journal-title":"Anim. Genet."},{"key":"2024061302171950200_DMM037804C16","doi-asserted-by":"publisher","first-page":"30769","DOI":"10.1074\/jbc.M111.267997","article-title":"Molecular and therapeutic characterization of anti-ectodysplasin A receptor (EDAR) agonist monoclonal antibodies","volume":"286","author":"Kowalczyk","year":"2011","journal-title":"J. Biol. Chem."},{"key":"2024061302171950200_DMM037804C17","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1016\/j.cytogfr.2014.01.004","article-title":"Ectodysplasin A (EDA)-EDA receptor signalling and its pharmacological modulation","volume":"25","author":"Kowalczyk-Quintas","year":"2014","journal-title":"Cytokine Growth Factor. Rev."},{"key":"2024061302171950200_DMM037804C18","doi-asserted-by":"publisher","first-page":"4273","DOI":"10.1074\/jbc.M113.535740","article-title":"Generation and characterization of function blocking anti-ectodysplasin A (EDA) monoclonal antibodies that induce ectodermal dysplasia","volume":"289","author":"Kowalczyk-Quintas","year":"2014","journal-title":"J. Biol. Chem."},{"key":"2024061302171950200_DMM037804C19","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1093\/jhered\/esi053","article-title":"Sparse and wavy hair: a new model for hypoplasia of hair follicle and mammary glands on rat chromosome 17","volume":"96","author":"Kuramoto","year":"2005","journal-title":"J. Hered."},{"key":"2024061302171950200_DMM037804C20","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1186\/1471-2156-12-91","article-title":"A rat model of hypohidrotic ectodermal dysplasia carries a missense mutation in the Edaradd gene","volume":"12","author":"Kuramoto","year":"2011","journal-title":"BMC Genet."},{"issue":"Suppl. 4","key":"2024061302171950200_DMM037804C21","doi-asserted-by":"publisher","first-page":"E52","DOI":"10.1177\/0194599813479772","article-title":"Panel 4: recent advances in otitis media in molecular biology, biochemistry, genetics, and animal models","volume":"148","author":"Li","year":"2013","journal-title":"Otolaryngol. Head Neck Surg."},{"key":"2024061302171950200_DMM037804C22","doi-asserted-by":"publisher","first-page":"863","DOI":"10.1007\/s003359900884","article-title":"YAC rescue of downless locus mutations in mice","volume":"9","author":"Majumder","year":"1998","journal-title":"Mamm. Genome"},{"key":"2024061302171950200_DMM037804C23","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1016\/S0165-5876(84)80030-0","article-title":"Ozena as presenting symptom of a rare and severe genetic disease: hypohidrotic ectodermal dysplasia","volume":"8","author":"Martini","year":"1984","journal-title":"Int. J. Pediatr. Otorhinolaryngol."},{"key":"2024061302171950200_DMM037804C24","doi-asserted-by":"publisher","first-page":"843","DOI":"10.1016\/j.otohns.2006.11.038","article-title":"Head and neck manifestations and quality of life of patients with ectodermal dysplasia","volume":"136","author":"Mehta","year":"2007","journal-title":"Otolaryngol. Head Neck Surg."},{"key":"2024061302171950200_DMM037804C25","doi-asserted-by":"publisher","first-page":"55","DOI":"10.2500\/ajr.2007.21.2989","article-title":"Rhinologic manifestations of ectodermal dysplasia","volume":"21","author":"Mehta","year":"2007","journal-title":"Am. J. Rhinol."},{"key":"2024061302171950200_DMM037804C26","doi-asserted-by":"publisher","first-page":"1405","DOI":"10.1002\/humu.20795","article-title":"Enhanced ectodysplasin-A receptor (EDAR) signaling alters multiple fiber characteristics to produce the East Asian hair form","volume":"29","author":"Mou","year":"2008","journal-title":"Hum. Mutat."},{"key":"2024061302171950200_DMM037804C27","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1007\/s00441-012-1490-9","article-title":"Differential localisation of BPIFA1 (SPLUNC1) and BPIFB1 (LPLUNC1) in the nasal and oral cavities of mice","volume":"350","author":"Musa","year":"2012","journal-title":"Cell Tissue Res."},{"key":"2024061302171950200_DMM037804C28","doi-asserted-by":"publisher","first-page":"1647","DOI":"10.1097\/00005537-200209000-00022","article-title":"Postnatal development of the eustachian tube glands","volume":"112","author":"Orita","year":"2002","journal-title":"Laryngoscope"},{"key":"2024061302171950200_DMM037804C29","doi-asserted-by":"publisher","first-page":"64","DOI":"10.3349\/ymj.1992.33.1.64","article-title":"Development of the mucociliary system in the eustachian tube and middle ear: murine model","volume":"33","author":"Park","year":"1992","journal-title":"Yonsei Med. J."},{"key":"2024061302171950200_DMM037804C30","first-page":"291","article-title":"Quantification of histochemical staining by color deconvolution","volume":"23","author":"Ruifrok","year":"2001","journal-title":"Anal. Quant. Cytol. Histol."},{"key":"2024061302171950200_DMM037804C31","doi-asserted-by":"publisher","first-page":"1604","DOI":"10.1056\/NEJMoa1714322","article-title":"Prenatal correction of X-linked hypohidrotic ectodermal dysplasia","volume":"378","author":"Schneider","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"2024061302171950200_DMM037804C32","doi-asserted-by":"publisher","first-page":"346","DOI":"10.1016\/j.jcpa.2004.11.001","article-title":"Ectodysplasin-1 deficiency in a German Holstein bull associated with loss of respiratory mucous glands and chronic rhinotracheitis","volume":"132","author":"Seeliger","year":"2005","journal-title":"J. Comp. Pathol."},{"key":"2024061302171950200_DMM037804C33","doi-asserted-by":"publisher","first-page":"1104","DOI":"10.1001\/archotol.130.9.1104","article-title":"Otologic manifestations of ectodermal dysplasia","volume":"130","author":"Shin","year":"2004","journal-title":"Arch, Otolaryngol, Head Neck Surg."},{"key":"2024061302171950200_DMM037804C34","first-page":"111","article-title":"Changes in the upper respiratory tract","volume":"1","author":"St","year":"1992","journal-title":"Pathobiology of the Aging Rat"},{"key":"2024061302171950200_DMM037804C35","doi-asserted-by":"publisher","first-page":"27567","DOI":"10.1074\/jbc.M109.042259","article-title":"Biological activity of ectodysplasin A is conditioned by its collagen and heparan sulfate proteoglycan-binding domains","volume":"284","author":"Swee","year":"2009","journal-title":"J. Biol. Chem."},{"key":"2024061302171950200_DMM037804C36","doi-asserted-by":"publisher","first-page":"2949","DOI":"10.1534\/g3.116.033225","article-title":"A splice defect in the EDA gene in dogs with an X-linked hypohidrotic ectodermal dysplasia (XLHED) phenotype","volume":"6","author":"Waluk","year":"2016","journal-title":"G3 (Bethesda)"}],"container-title":["Disease Models &amp; Mechanisms"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1242\/dmm.037804","content-type":"unspecified","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.biologists.com\/dmm\/article-pdf\/doi\/10.1242\/dmm.037804\/3483457\/dmm037804.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.biologists.com\/dmm\/article-pdf\/doi\/10.1242\/dmm.037804\/3483457\/dmm037804.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,13]],"date-time":"2024-06-13T02:18:22Z","timestamp":1718245102000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/dmm\/article\/12\/4\/dmm037804\/19881\/Role-of-ectodysplasin-signalling-in-middle-ear-and"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,4,1]]},"references-count":36,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2019,4,1]]}},"URL":"https:\/\/doi.org\/10.1242\/dmm.037804","relation":{},"ISSN":["1754-8411","1754-8403"],"issn-type":[{"value":"1754-8411","type":"electronic"},{"value":"1754-8403","type":"print"}],"subject":[],"published":{"date-parts":[[2019,4,1]]},"article-number":"dmm037804"}}