The WFS1 gene, responsible for low frequency sensorineural hearing loss and Wolfram syndrome, is expressed in a variety of inner ear cells

Abstract

Heterozygous mutations in the WFS1 gene are responsible for autosomal dominant low frequency hearing loss at the DFNA6/14 locus, while homozygous or compound heterozygous mutations underlie Wolfram syndrome. In this study we examine expression of wolframin, the WFS1-gene product, in mouse inner ear at different developmental stages using immunohistochemistry and in situ hybridization. Both techniques showed compatible results and indicated a clear expression in different cell types of the inner ear. Although there were observable developmental differences, no differences in staining pattern or gradients of expression were observed between the basal and apical parts of the cochlea. Double immunostaining with an endoplasmic reticulum marker confirmed that wolframin localizes to this organelle. A remarkable similarity was observed between cells expressing wolframin and the presence of canalicular reticulum, a specialized form of endoplasmic reticulum. The canalicular reticulum is believed to be involved in the transcellular movements of ions, an important process in the physiology of the inner ear. Although there is nothing currently known about the function of wolframin, our results suggest that it may play a role in inner ear ion homeostasis as maintained by the canalicular reticulum.Keywords WFS1 · Inner ear · Immunohistochemistry · In situ hybridization · Canalicular reticulum Recessive mutations in the WFS1 gene also cause Wolfram syndrome, known by the acronym DIDMOAD to reflect the syndrome phenotype of diabetes insipidus, diabetes mellitus, optic atrophy, and deafness (Inoue et al. 1998;Strom et al. 1998). In contrast to the low frequency K. Cryns and S. Thys contributed equally K. Cryns · S. Thys · L. Van Laer · G. Van Camp ( ) )

Variants in WFS1 and Other Mendelian Deafness Genes Are Associated with Cisplatin-Associated Ototoxicity

“…WFS1 is expressed in a variety of tissues including inner ear sensory cells such as outer hair cells, spiral ganglion neurons, and cochlear lateral wall fibrocytes (35,36). The minor allele of rs62283056 (frequency 0.21 in the GWAS cohort) associates with both increased hearing loss (Fig.…”

Pharmacogenomics of Cisplatin‐Induced Ototoxicity: Successes, Shortcomings, and Future Avenues of Research

“…51,52 Thus, the less severe impact of the regulatory variant on WFS1 function may place individuals at increased risk for hearing loss when the effect of the variant is amplified in the presence of cisplatin. Functional support was provided for the gene through data that showed that WFS1 is expressed in inner ear sensory cells 53,54 and that WFS1 expression correlates with cisplatin-induced cytotoxicity. 47,48 Initial studies by Xu et al 24 and Drögemöller et al, 37 which investigated the association of rs62283056 with CIO, were unable to replicate these findings.…”

Wolfram syndrome and WFS1 gene

“…The expression of wolframin is widely distributed in different cochlear cell types, including inner and outer hair cells, a variety of supporting cells, and cells of the lateral wall, spiral ganglion, and vestibule (57). It has been localized in the mouse coclea at different developmental stages from birth to postnatal day 35 (57). Thus, it is possible that WFS1 contributes to both the development and maintenance of cells in the auditory system including the coclea.…”

“…In the inner ear, wolframin may help maintain the proper levels of calcium ions or other charged particles that are essential for hearing (57).…”