Inner Ear Morphology Is Perturbed in Two Novel Mouse Models of Recessive Deafness

Kerry A Miller,Louise H Williams,Hans-Henrik M Dahl,Michael Kuiper,Shehnaaz S M Manji,Elizabeth Rose,Tiansen Li

doi:10.1371/journal.pone.0051284

Abstract

Human MYO7A mutations can cause a variety of conditions involving the inner ear. These include dominant and recessive non-syndromic hearing loss and syndromic conditions such as Usher syndrome. Mouse models of deafness allow us to investigate functional pathways involved in normal and abnormal hearing processes. We present two novel mouse models with mutations in the Myo7a gene with distinct phenotypes. The mutation in Myo7aI487N/I487N ewaso is located within the head motor domain of Myo7a. Mice exhibit a profound hearing loss and manifest behaviour associated with a vestibular defect. A mutation located in the linker region between the coiled-coil and the first MyTH4 domains of the protein is responsible in Myo7aF947I/F947I dumbo. These mice show a less severe hearing loss than in Myo7aI487N/I487N ewaso; their hearing loss threshold is elevated at 4 weeks old, and progressively worsens with age. These mice show no obvious signs of vestibular dysfunction, although scanning electron microscopy reveals a mild phenotype in vestibular stereocilia bundles. The Myo7aF947I/F947I dumbo strain is therefore the first reported Myo7a mouse model without an overt vestibular phenotype; a possible model for human DFNB2 deafness. Understanding the molecular basis of these newly identified mutations will provide knowledge into the complex genetic pathways involved in the maintenance of hearing, and will provide insight into recessively inherited sensorineural hearing loss in humans.

Highlights

A fully functional auditory system is required by humans to communicate and to perceive the surrounding environment
It is well understood that mutations in the MYO7A gene can underlie certain forms of syndromic and non-syndromic deafness in the human population, non-syndromic dominant (DFNA11) and recessive (DFNB2) deafness and Usher Syndrome type 1B (USH1B)
Myosin VIIA was the first gene identified as a contributing factor to hearing loss in a genetic screen of mutations that lead to inner ear defects in the mouse [39], and until now 9 mouse models with mutations in the Myo7a gene have been published [19,39,40,41]

Summary

Introduction

A fully functional auditory system is required by humans to communicate and to perceive the surrounding environment. Disruption of this system, and the closely associated vestibular system, can lead to severe impairments to an individual’s hearing and balance, and can be attributed to genetic and/or environmental factors. Hearing loss can be associated with additional clinical abnormalities, as seen in Pendred and Usher syndromes [3,4,5]. In 70% of cases inherited hearing loss is non-syndromic, presenting as the only clinical feature [1], and in 80% of these cases is inherited in an autosomal recessive mode [6]

Methods

Results

Conclusion