Gene Associated with Severe Hearing Loss Uncovered

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Organ of Corti, SEM - Cochlea cells - inner ear
Colored scanning electron micrograph (SEM) view of the top surface of the organ of Corti in the cochlea of the inner ear. There is a row of inner hair cells (yellow) across top and three rows of outer hair cells (crescent shaped).

Researchers at the University of Pennsylvania have discovered that loss of function mutations in a gene called GAS2 can cause severe hearing loss, as the proteins encoded by this gene help stabilize the inner ear.

In a study in a mouse model, Douglas Epstein, Ph.D., a professor based in the Perelman School of Medicine, and colleagues showed that the GAS2 protein plays a crucial role in making sure that support cells in the inner ear are stiff enough to amplify incoming sound correctly.

“Anatomists 150 years ago took pains to draw these support cells with the details of their unique internal structures, but it’s only now, with this discovery about GAS2, that we understand the importance of those structures for normal hearing,” said Epstein, who is the lead author of the paper describing the research, published in the journal Developmental Cell.

Early hearing loss affects between 2-6 per 1000 children, depending on country of birth. Around half of these cases are genetic and although hearing aids and cochlear implants have improved beyond all recognition in recent years, they are not normally able to completely restore hearing to normal levels.

Epstein’s group previously discovered that the GAS2 gene plays a role in hearing loss and created a genetically modified Gas2-knockout mouse model to more closely analyze the molecular and physiological causes of this loss.

They found that the mice were severely hearing impaired (99.9% loss of acoustic energy), but appeared to have normal looking inner ears and structures. However, on further research the team found that structurally important microtubule bundles were not tightly bound in pillar cells and Deiters’ cells in the inner ear that normally express the Gas2 protein.

In mice without hearing problems, these cells normally contain tightly bound microtubules that help stiffen the cells and support the amplification of sound in the inner ear detected via movement of outer hair cells. The lack of this stiffness in the pillar and Deiters’ cells seems to have catastrophic consequences for hearing in the mice by severely impacting the ability of the inner ear cells to detect and amplify sounds.

“We observed that some of Deiters’ cells in the Gas2-knockout mice even buckled under the tension of the rapid movements of the outer hair cells,” Epstein said.

Loss of function mutations in the GAS2 gene causing hearing loss have also recently been found in humans, although the wider prevalence of these variants around the world is uncertain. Variants in this gene may also be implicated in more common, slower onset, adult hearing loss, but confirmation is needed of this.

Epstein thinks that a gene therapy could be developed to treat these individuals in the future. “In many genetic hearing loss conditions, the affected cells are permanently damaged or die, but in this one, the affected cells are intact and conceivably could be restored to normal or near-normal by restoring GAS2 function,” he said.

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