Effects of the TECTB-C225Y Variant in the Inner Ear

Harvard Medical School, Boston MA

Investigators

Abstract

Project Summary/Abstract Hearing loss is the most prevalent human sensory deficit. Sound transduction takes place in the organ of Corti of the inner ear. It is lined with specialized sensory hair cells with mechanosensitive hair bundles formed by actin- filled stereocilia. Stimulation of both hair cell types is conveyed through the shear of the tectorial membrane, an extracellular matrix which resides above the sensory hair cells. TECTB encodes for one of the major non- collagenous components of the tectorial membrane and has also been localized to the otolithic membrane. Investigation of autosomal-dominant hearing loss in a Nicaraguan family has revealed a point mutation of TECTB, TECTB-C225Y. To investigate the effect of this point mutation, we have developed a Tectb-C225Y mouse model. Our goal is to assess the phenotype of the Tectb-C225Y mouse to determine if it recapitulates the phenotype observed in patients and to more closely investigate the effect of this point mutation on hearing. This study of TECTB-C225Y variant using three closely aligned Specific Aims will help our understanding of its role in the inner ear and aid in developing future therapeutic approaches. Specific Aim 1 is to characterize the effect of the TECTB-C225Y variant on hearing function in mice. This will be accomplished through assessing auditory function in TectbC225Y/C225Y, TectbC225Y/+, and wild type mice through ABR and DPOAE testing (1.1) and performing histological assessment of the inner ear (1.2) Our preliminary data obtained from Tectb-C225Y mice show elevation of hearing thresholds in TectbC225Y/C225Y mice. Supporting this, preliminary histological comparison of the tectorial membranes of mutant and wild type animals revealed structural differences in TectbC225Y/+ and TectbC225Y/C225Y mice. Our preliminary data from auditory tests of TectbC225Y/+ mice indicate hearing highly similar to that of wild types, even at 9 months. In contrast, patients with a single allele for the TECTB-C225Y variant exhibit an easily detectable progressive hearing loss. The discrepancy in the hearing phenotype presentation between humans and our animal model may be attributed to differences in noise exposure. Thus, our Specific Aim 2 is to evaluate the effect of noise exposure on Tectb-C225Y mice. This will be accomplished by assessing auditory function in TectbC225Y/+ and wild type noise exposed mice through ABR and DPOAE testing (2.1) and performing histological analysis of noise exposed inner ears (2.2). The atomic structure of TECTB has yet to be solved and there is no definitive basis for predicting the precise changes in the TECTB-C225Y variant. Thus, in addition to characterizing physiological changes to the tectorial membrane, our Specific Aim 3 is to characterize the atomic structure of the TECTB protein.