Abstract
Otitis media (OM), inflammation of the middle ear, is a common cause of hearing loss in children and in patients with many different syndromic diseases. Studies of the human population and mouse models have revealed that OM is a multifactorial disease with many environmental and genetic contributing factors. Here, we report on otitis media-related hearing loss in asj (ages with stiffened joints) mutant mice, which bear a point mutation in the Enpp1 gene. Auditory-evoked brainstem response (ABR) measurements revealed that around 90% of the mutant mice (Enpp1asj/asj) tested had moderate to severe hearing impairment in at least one ear. The ABR thresholds were variable and generally elevated with age. We found otitis media with effusion (OME) in all of the hearing-impaired Enpp1asj/asj mice by anatomic and histological examinations. The volume and inflammatory cell content of the effusion varied among the asj mutant mice, but all mutants exhibited a thickened middle ear epithelium with fibrous polyps and more mucin-secreting goblet cells than controls. Other abnormalities observed in the Enpp1 mutant mice include over-ossification at the round window ridge, thickened and over-calcified stapedial artery, fusion of malleus and incus, and white patches on the inside of tympanic membrane, some of which are typical symptoms of tympanosclerosis. An excessive yellow discharge was detected in the outer ear canal of older asj mutant mice, with 100% penetrance by 5 months of age, and contributes to the progressive nature of the hearing loss. This is the first report of hearing loss and ear pathology associated with an Enpp1 mutation in mice. The Enpp1asj mutant mouse provides a new animal model for studying tympanosclerotic otitis and otitis media with effusion, and also provides a specific model for the hearing loss recently reported to be associated with human ENPP1 mutations causing generalized arterial calcification of infancy and hypophosphatemic rickets.
Highlights
IntroductionWhile many genes have been discovered that underlie Mendelian forms of sensorineural hearing loss (http://hereditaryhearingloss.org/), most cases of conductive hearing loss, often causedPLOS ONE | DOI:10.1371/journal.pone.0168159 December 13, 2016Hearing Loss in Enpp Mutant Mice by otitis media and tympanosclerosis, have complex and poorly understood etiologies
While many genes have been discovered that underlie Mendelian forms of sensorineural hearing loss, most cases of conductive hearing loss, often causedPLOS ONE | DOI:10.1371/journal.pone.0168159 December 13, 2016Hearing Loss in ectonucleotide pyrophosphatase/phosphodiesterase 1 gene (Enpp1) Mutant Mice by otitis media and tympanosclerosis, have complex and poorly understood etiologies
Hearing in the Enpp1 mutant mice and age-matched controls was evaluated by Auditory-evoked brainstem response (ABR) threshold analysis
Summary
While many genes have been discovered that underlie Mendelian forms of sensorineural hearing loss (http://hereditaryhearingloss.org/), most cases of conductive hearing loss, often causedPLOS ONE | DOI:10.1371/journal.pone.0168159 December 13, 2016Hearing Loss in Enpp Mutant Mice by otitis media and tympanosclerosis, have complex and poorly understood etiologies. Heritability studies have shown that genetic factors can play an important role in otitis media susceptibility, but few contributing genes have been identified in human populations [1]. In contrast to human studies, a growing number of mouse mutations have been identified that manifest a high incidence of otitis media, including Eya, Tlr, p73, MyD88, Fas, E2f4, Plg, Fbxo, Evi1 [1,2], Sh3pxd2b [3], Rpl38 [4], Isl1 [5], Chd7 [6], Lmna1 [7], Phex [8], Oxgr1 [9], Tgif1 [10], and Mcph1 [11]. The wide diversity of these genes and their mutant pathologies, including craniofacial abnormalities with Eustachian tube malformations and innate immune response defects, underscores the complex nature of otitis media
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
