Anatomical and Functional Abnormalities of the Lateral Semicircular Canals in a Pendrin-Deficient Mouse Model

Abstract

Pendrin, encoded by the SLC26A4 gene, is an anion exchanger protein expressed in the epithelial cells of inner ear. Clinically, the absence of pendrin results in hearing loss associated with enlarged vestibular aqueduct

it is simultaneously observed with dizziness and postural imbalance. The aim of this study was to investigate the quantitative responses of vestibulo-ocular reflex (VOR) and anatomical abnormalities of the lateral semicircular canal (LSC) in a pendrin-deficient mice strain. The mice strain consisted of wild type mice and three distinct genetic conditions: homozygous knockout mice, transgenic mice with doxycycline-inducible expression of Slc26a4, and heterozygotes. Hearing and balancing systems were evaluated by auditory brainstem response, sinusoidal harmonic acceleration test, and histology of the LSC. All Slc26a4 homozygous knockout mice showed total deafness, whereas the remaining strains had normal hearing, indicating all-or-none phenotype of auditory function. The sinusoidal harmonic acceleration test exhibited minimal VOR responses in homozygotes and intermediate responses in transgenic mice and heterozygotes compared with normal controls. This outcome implies a pendrin dose-dependent pattern of vestibular dysfunction. Vacuolar replacement and absence of calretinin expression of vestibular hair cells in the LSC were identified in homozygotes. However, no apparent difference in inner ear architectures among wild-type, heterozygous, and transgenic mice were identified. These results suggest that mutations of Slc26a4 gene in mouse models induce diverse functional deficits of the LSC and vestibular diseases with variable manifestations.