serval:BIB_4103E7371D49
Role of ectodysplasin signalling in middle ear and nasal pathology in rat and mouse models of hypohidrotic ectodermal dysplasia.
10.1242/dmm.037804
000467597600004
31028034
Del-Pozo
J.
author
MacIntyre
N.
author
Azar
A.
author
Headon
D.
author
Schneider
P.
author
Cheeseman
M.
author
article
2019-04-25
Disease models & mechanisms
1754-8411
1754-8403
journal
12
4
Patients with mutations in the ectodysplasin receptor signalling pathway genes - the X-linked ligand ectodysplasin-A (EDA), the receptor EDAR or the receptor adapter EDARADD - 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 (Eda <sup>Ta</sup> ) and downless (Edar <sup>dl-J/dl-J</sup> ) have rhinitis and otitis media due to loss of submucosal glands in the upper airway. We report that prenatal correction of EDAR signalling in Eda <sup>Ta</sup> 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 Edaradd <sup>swh/swh</sup> than those in unaffected heterozygous Edaradd <sup>swh/+</sup> 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.
Animals
Antibodies/pharmacology
Disease Models, Animal
Ear, Middle/metabolism
Ear, Middle/pathology
Ectodermal Dysplasia 1, Anhidrotic/metabolism
Ectodermal Dysplasia 1, Anhidrotic/pathology
Ectodysplasins/metabolism
Female
Hyalin/metabolism
Male
Mice
Nasopharyngitis/complications
Nasopharyngitis/pathology
Nasopharynx/drug effects
Nasopharynx/pathology
Nose/pathology
Otitis Media/complications
Otitis Media/pathology
Phenotype
Rats
Receptors, Ectodysplasin/agonists
Receptors, Ectodysplasin/metabolism
Rhinitis/complications
Signal Transduction
Auditory-tube submucosal gland
EDAR signalling
Eda mouse
Edaradd rat
Otitis media
XLHED
eng
60_published
true
peer-reviewed
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: epublish
University of Lausanne
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