Slc26a4-insufficiency causes fluctuating hearing loss and stria vascularis dysfunction

Abstract

SLC26A4 mutations can cause a distinctive hearing loss phenotype with sudden drops and fluctuation in patients. Existing Slc26a4 mutant mouse lines have a profound loss of hearing and vestibular function, with severe inner ear malformations that do not model this human phenotype. In this study, we generated Slc26a4-insufficient mice by manipulation of doxycycline administration to a transgenic mouse line in which all Slc26a4 expression was under the control of doxycycline. Doxycycline was administered from conception to embryonic day 17.5, and then discontinued. Auditory brainstem response thresholds showed significant fluctuation of hearing loss from 1 through 3 months of age. The endocochlear potential, which is required for inner ear sensory cell function, correlated with auditory brainstem response thresholds. We observed degeneration of stria vascularis intermediate cells, the cells that generate the endocochlear potential, but no other abnormalities within the cochlea. We conclude that fluctuations of hearing result from fluctuations of the endocochlear potential and stria vascularis dysfunction in Slc26a4-insufficient mouse ears. This model can now be used to test potential interventions to reduce or prevent sudden hearing loss or fluctuation in human patients. Our strategy to generate a hypomorphic mouse model utilizing the tet-on system will be applicable to other diseases in which a hypomorphic allele is needed to model the human phenotype.

Development of the stria vascularis and potassium regulation in the human fetal cochlea: Insights into hereditary sensorineural hearing loss

“…In Pendred syndrome, SLC26A4 [MIM 605646] mutations account for the majority of cases (Everett et al, 1997). The dysfunction of its protein, PENDRIN, results in loss of KCNJ10 expression in the melanocytes of the stria vascularis and subsequent loss of the endocochlear potential (Wangemann et al, 2004; Ito et al, 2014). However, mutations in KCNJ10 itself have also been linked directly to Pendred syndrome (Yang et al, 2009).…”

NLRP3 mutation and cochlear autoinflammation cause syndromic and nonsyndromic hearing loss DFNA34 responsive to anakinra therapy

“…Sections were counterstained with Alexa Fluor 568 phalloidin (Life Technologies) diluted 1:500. Whole-mounted cochlear tissues from Cx3cr1 GFP/+ mice were immunostained with anti-CD34 or anti-F4/80 antibodies, as described previously (27,28), with some modifications. RT-PCR Analyses.…”

“…Recent studies have demonstrated that the mouse cochlea harbors cells that are immunoreactive with immune cell-specific markers under normal resting conditions (25)(26)(27), as well as in pathogenic disorders of hearing. In an Slc26a4-insufficient mouse model of hearing loss in human DFNB4 nonsyndromic deafness and Pendred syndrome, hearing loss is associated with an increase in staining of macrophage/ monocyte-like cells in the cochlea (28). It is unknown if these cells mediate local innate immune responses through activation of the NLRP3 inflammasome within the cochlea.…”

Progressive irreversible hearing loss is caused by stria vascularis degeneration in an Slc26a4-insufficient mouse model of large vestibular aqueduct syndrome

“…This phenotype closely models the hearing loss associated with EVA in humans, which is typically unilateral or asymmetric (Jackler and De La Cruz 1989, Levenson, Parisier et al 1989, Griffith and Wangemann 2011). We characterized the natural history and pathogenesis of hearing loss after one month of age in Tg[E];Tg[R]; Slc26a Δ/Δ mice which received doxycycline from conception until E17.5 (DE17.5) (Ito, Li et al 2014). The mice had fluctuating hearing loss between 1 and 6 months of age with an overall downward progression after 6 months of age.…”