Genetics of hearing and deafness

Abstract

This article is a review of the genes and genetic disorders that affect hearing in humans and a few selected mouse models of deafness. Genetics is playing an increasingly critical role in the practice of medicine. This is not only in part to the importance that genetic knowledge has on traditional genetic diseases but also in part to the fact that genetic knowledge provides an understanding of the fundamental biological process of most diseases. The proteins coded by the genes related to hearing loss (HL) are involved in many functions in the ear, such as cochlear fluid homeostasis, ionic channels, stereocilia morphology and function, synaptic transmission, gene regulation, and others. Mouse models play a crucial role in understanding of the pathogenesis associated with these genes. Different types of familial HL have been recognized for years; however, in the last two decades, there has been tremendous progress in the discovery of gene mutations that cause deafness. Most of the cases of genetic deafness recognized today are monogenic disorders that can be broadly classified by the mode of inheritance (i.e., autosomal dominant, autosomal recessive, X-linked, and mitochondrial inheritance) and by the presence of associated phenotypic features (i.e., syndromic; and nonsyndromic). In terms of nonsyndromic HL, the chromosomal locations are currently known for ∼ 125 loci (54 for dominant and 71 for recessive deafness), 64 genes have been identified (24 for dominant and 40 for recessive deafness), and there are many more loci for syndromic deafness and X-linked and mitochondrial DNA disorders (http://hereditaryhearingloss.org). Thus, today's clinician must understand the science of medical genetics as this knowledge can lead to more effective disease diagnosis, counseling, treatment, and prevention.

Fig. 1

Cellular expression pattern of connexin 26 in the inner ear of a mouse and the effect of conditional knockout of it on the morphology of the organ of Corti (apical turn). A: Combined differential interference contrast (DIC) imaging and immunolabeling of connexin 26 obtained from a cochlear section. An enlarged view for the area indicated by a white box is given in (B). Scale bar represents ~ 100 μm. B: Immunlabeling of connexin 26 obtained from a section of the organ of Corti. The section is counterstained with DAPI to indicate the location of cell nuclei. Major landmarks of the organ of Corti are labeled. Scale bar represents ~ 100 μm. C: Normal morphology of the organ of Corti (apical turn) of a WT mouse at P14. Runnel of Corti is opened at this stage of development. Scale bar represents ~ 100 μm. D: Typi cal morphology of the apical turn organ of Corti of a conditional connexin 26 knockout mouse. Both inner (big arrowhead) and outer (small arrows) hair cells are intact. The tunnel of Corti remains closed. Scale bar represents ~ 100 μm.

Fig. 2

High-resolution computed tomography of the temporal bone, with axial cuts of the left ear, showing an enlarged vestibular aqueduct.

Fig. 3

High-resolution computed tomography of the temporal bone, with axial cuts of the right ear at the level of the modiolus, of a boy with mixed hearing loss: the cochlear canal is enlarged creating abnormal patency between the cochlear fluids and the subarachnoid space. This child has X-linked mixed hearing loss DFN4.