According to the CDC, 50–60% of hearing loss in babies is due to genetic causes. However, there are also a number of things in the environment that can cause hearing loss. In some cases, hearing loss is caused when both genes and the environment work together. A new mouse study by researchers at the Perelman School of Medicine at the University of Pennsylvania demonstrated that a gene called GAS2 plays a key role in normal hearing, and its absence causes severe hearing loss.
The new study, “Cochlear supporting cells require GAS2 for cytoskeletal architecture and hearing,” is published in the journal Developmental Cell. The researchers showed that inner ear support cells lacking functional GAS2 lose their amplifier abilities, causing severe hearing impairment in mice.
“In mammals, sound is detected by mechanosensory hair cells that are activated in response to vibrations at frequency-dependent positions along the cochlear duct,” wrote the researchers. “We demonstrate that inner ear supporting cells provide a structural framework for transmitting sound energy through the cochlear partition.”
The study’s senior author Douglas J. Epstein, PhD, professor of genetics at Penn Medicine, explained: “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.”
At present, treatments for genetic hearing loss include hearing aids and/or cochlear implants. While hearing aids and cochlear implants are helpful treatments, they do not restore hearing to normal levels.
Epstein’s team previously 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. The team then developed a line of mice in which the gene had been knocked out of the genome to determine Gas2’s role.
The researchers were perplexed to observe that the Gas2-knockout mice had inner ears with cells and structures that seemed normal. However, the animals turned out to be severely hearing-impaired.
The experiments revealed that the pillar and Deiters’ cells’ loss of stiffness, due to the absence of Gas2, severely degrades the sound-amplifying properties of the outer hair cells they support.
“Humans and mice with mutations in GAS2, encoding a cytoskeletal regulatory protein, exhibit hearing loss due to disorganization and destabilization of microtubule bundles in pillar and Deiters’ cells, two types of inner ear supporting cells with unique cytoskeletal specializations. Failure to maintain microtubule bundle integrity reduced supporting cell stiffness, which in turn altered cochlear micromechanics in Gas2 mutants,” noted the researchers.
The experiments included imaging of propagating sound waves in the inner ears of live Gas2-knockout and normal mice, conducted by collaborator John Oghalai, MD, chair and professor of otolaryngology, head and neck surgery, at the Keck School of Medicine of USC, and his team.
The researchers could find no reports of GAS2-associated congenital hearing loss in medical literature. However, Hannie Kremer, PhD, professor and chair of molecular otogenetics at Radboud University Medical Center in the Netherlands, emailed Epstein that she and her team had been studying 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.
The study establishes GAS2 as a potential new hearing loss gene in humans that is the first one known to affect the mechanical properties of inner ear support cells.
“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,” Epstein added.
Epstein believes it has the potential to be a candidate study for gene therapy, but noted such a gene therapy might be useful not only in more obvious cases of hearing loss in early childhood, but also in cases in which inherited mutations lead to a slower development of hearing loss in adulthood.