Role of Ectodysplasin signalling in middle ear and nasal pathology in rat and mouse models of hypohidrotic ectodermal dysplasia

Jorge Del-Pozo, Neil Macintyre, Ali Anvari Azar, Denis Headon, Pascal Schneider, Michael Cheeseman

Research output: Contribution to journalArticlepeer-review

Abstract

Patients with mutations in the Ectodysplasin receptor signalling pathway genes, the X-linked ligand EDA, the receptor EDAR or the receptor adapter EDARADD, have Hypohidrotic Ectodermal Dysplasia (HED). In addition to having impaired
development of teeth, hair and eccrine sweat gland, 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 agonist mAbEDAR1 antibody rescues the auditory-tube submucosal glands and prevents otitis media, rhinitis and nasopharyngitis. The sparse and wavy haired rat strain carries a mutation in Edaradd gene and has similar cutaneous HED
phenotypes to murine models. We report that auditory-tube submucosal glands are smaller in the homozygous mutant Edaraddswh/swh than those in unaffected
heterozygous Edaraddswh/+ rats and this predisposes 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 hypomorphic as well as null mutations in EDAR signalling pathway genes may predispose to otitis media in human patients. In addition this work suggests that the recent successful prenatal treatment of 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 that is common in children.
Original languageEnglish
Article numberdmm037804
JournalDisease Models and Mechanisms
Volume12
Issue number4
DOIs
Publication statusPublished - 25 Apr 2019

Keywords

  • EDAR signalling
  • Eda mouse
  • Edaradd rat
  • XLHED
  • Auditory-tube submucosal gland
  • Otitis media

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