Tight junction proteins and the etiology of hereditary hearing loss in humans and animal models

Multicellular organisms have separate compartments of different compositions. In the cochlea of the inner ear separation between endolymph and perilimph, two compartments with very different sodium and potassium ion concentrations, is necessary for normal hearing. This compartmentalization is achieved by tight junctions (TJs), which form the major selective barrier of the paracellular pathway between epithelial cells. TJ strands contain at least five types of membrane-spanning proteins. To date, mutations in five different TJ membrane integral proteins have been associated with hearing loss. Mutations in claudin 14 and in tricellulin are associated with hereditary hearing loss in humans. Claudin 9-, claudin 11- and claudin 14-mutant mice are deaf. In zebrafish, a mutation of the cldnj gene leads to abnormal auditory and vestibular functions. There are different etiologies for hearing loss associated with each of these proteins, including hair cell loss, reduced endocochlear potentials, and abnormal embryonic development of the inner ear. Nevertheless, in all cases the underlying cause is dysfunction of the paracellular barrier. These findings elucidate the crucial role played by TJs in the auditory apparatus, and enhance our understanding of the hearing process. This knowledge will be further enhanced by identification of hearing-related phenotypes associated with additional TJ proteins and generation of additional animal models in years to come.