Discovery of a new genetic cause of hearing loss illuminates how inner ear works – India Education Diary

A gene calledGAS2plays a key role in normal hearing, and its absence causes severe hearing loss, according to a study led by researchers in the Perelman School of Medicine at the University of Pennsylvania.

The researchers, whose findings arepublished online today inDevelopmental Cell, discovered that the protein encoded byGAS2is crucial for maintaining the structural stiffness of support cells in the inner ear that normally help amplify incoming sound waves. They showed that inner ear support cells lacking functionalGAS2lose their amplifier abilities, causing severe hearing impairment in mice. The researchers also identified people who haveGAS2mutations and severe hearing loss.

Anatomists 150 years ago took pains to draw these support cells with the details of their unique internal structures, but its only now, with this discovery aboutGAS2, that we understand the importance of those structures for normal hearing, said study senior authorDouglas J. Epstein, PhD, professor of genetics at Penn Medicine.

Two to three of every 1,000 children in the United States are born with hearing loss in one or both ears. About half of these cases are genetic. Although hearing aids and cochlear implants often can help, these devices seldom restore hearing to normal.

One of the main focuses of the Epstein laboratory at Penn Medicine is the study of genes that control the development and function of the inner eargenes that are often implicated in congenital hearing loss. The inner ear contains a complex, snail-shaped structure, the cochlea, that amplifies the vibrations from sound waves, transduces them into nerve signals, and sends those signals toward the auditory cortex of the brain.

Unraveling the role ofGas2in hearing

A few years ago, Epsteins team discovered thatGas2, the mouse version of humanGAS2, is switched on in embryos by another gene known to be critical for inner ear development. To determineGas2s role in that development, the team developed a line of mice in which the gene had been knocked out of the genome and called themGas2-knockout mice.

Alex Rohacek, PhD, a former graduate student in the Epstein lab, was puzzled to observe that theGas2-knockout mice had inner ears with cells and structures that seemed quite normal. However, the animals, when tested, turned out to be severely hearing-impaired, with deficits at high sound frequencies of up to 50 decibelsequivalent to a loss of 99.999 percent of the normal acoustic energy.

Tingfang Chen, PhD, a postdoctoral fellow and co-first author on the study, determined thatGas2is normally active within inner-ear support cells called pillar cells and Deiters cells. In these cells, the protein encoded by the gene binds to flexible, tube-like structures called microtubules in a way that bundles and stabilizes them, effectively stiffening the cells.

With help from the collaborating team ofBenjamin L. Prosser, PhD, assistant professor of Physiology at Penn Medicine and an expert on microtubules, the researchers discovered that when pillar cells and Deiters cells lackGas2, their microtubule bundles tend to come apart, dramatically reducing the stiffness of the cells.

That turns out to have dire implications for hearing. Within the inner ear, pillar cells and Dieters cells help form the basic structure of the cochlea and serve as physical supports for cells called outer hair cells. The outer hair cells move in response to incoming acoustical vibrationsessentially to provide a crucial amplification of that sound energy. The experiments revealed that the pillar and Deiters cells loss of stiffness, due to the absence ofGas2, severely degrades the sound-amplifying properties of the outer hair cells they support.

We observed that some of Deiters cells in theGas2-knockout mice even buckled under the tension of the rapid movements of the outer hair cells, Epstein said.

The experiments included sophisticated imaging of propagating sound waves in the inner ears of liveGas2-knockout and normal mice, conducted by collaboratorJohn Oghalai, MD, chair and professor of otolaryngology-head and neck surgery at the Keck School of Medicine of USC, and his team.

GAS2also causes human hearing loss

Curiously, the researchers could find no reports ofGAS2-associated congenital hearing loss in the medical literature. Even when they canvassed colleagues around the world who run hearing-loss clinics, they came up empty-handed.

Then one day,Hannie Kremer, PhD, professor and chair of molecular otogenetics at Radboud University Medical Center in the Netherlands, emailed Epstein. 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 genesbut each carried two mutant copies ofGAS2.

The study therefore establishesGAS2as a very probable new hearing loss gene in humansthe first one known to affect the mechanical properties of inner ear support cells.

The prevalence of hearing loss in people due toGAS2mutations remains to be determined, but Epstein noted that this type of congenital hearing loss is nevertheless an attractive target for a future gene therapy.

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 restoringGAS2function, he said.

He added that such a gene therapy might be useful not only in more obvious cases of hearing loss in early childhood, but also in casesperhaps more numerousin which inherited mutations lead to a slower development of hearing loss in adulthood.

Funding was provided by the National Institutes of Health (R01 DC006254, R01 DC014450, R01 DC013774, R01 DC017741, R01 HL133080), the Boucai Innovation Fund in Auditory Genomics, the National Science Foundation (15-48571), and the Heinsius Houbolt Foundation.

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Discovery of a new genetic cause of hearing loss illuminates how inner ear works - India Education Diary

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