Researchers at the Perelman School of Medicine at the University of Pennsylvania (Penn Medicine) in Philadelphia have discovered that the gene GAS2 plays a key role in normal hearing in both mice and humans, and that its absence causes severe hearing loss, according to a new study published in Developmental Cell and led by (Dev. Cell. 2021;56:P1526-1540).
The researchers found that the protein encoded by GAS2 is crucial for maintaining the structural stiffness of support cells in the inner ear that normally help amplify incoming sound waves. Inner ear support cells lacking functional GAS2 lose their amplifier abilities, causing severe hearing impairment in mice. The researchers also identified people who haveGAS2 mutations and severe hearing loss.
“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 study senior author Douglas J. Epstein, PhD, professor of genetics at Penn Medicine, in a press release.
Previously, Dr. Epstein’s team discovered that Gas2, the mouse version of human GAS2, is switched on in embryos by another gene known to be critical for inner ear development. To determine Gas2’s role in that development, the team developed Gas2-knockout mice, in which the gene had been knocked out of the genome. Gas2-knockout mice had inner ear cells and structures that appeared normal, but when tested were severely hearing impaired, with deficits at high sound frequencies of up to 50 decibels. The researchers discovered that when pillar cells and Deiters’ cells lack Gas2, the stiffness of the cells was dramatically reduced, affecting the basic structure of the cochlea and the physical supports for outer hair cells.
Although the researchers could find no reports of GAS2-associated congenital hearing loss in the medical literature, they did find a Somalian family in which four of the siblings had severe hearing loss from early life. The affected family members had no mutations in known hearing-loss genes, but each carried two mutant copies of GAS2.
Although the prevalence of hearing loss in people due to GAS2 mutations remains to be determined, Dr. Epstein noted that it is an attractive target for a future gene therapy. “In many genetic hearing loss conditions, the affected cells are permanently damaged or die,” he said. “But in this one, the affected cells are intact and conceivably could be restored to normal or near-normal by restoring GAS2 function.”