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Harvard Medical School Examines Inherited Hearing Loss and Deafness

Rising from the top surface of each of the specialized receptor cells in our inner ears is a bundle of sensory cilia that responds to the movement of sound. As sensitive as they are fragile, these cilia can move to wisps of sound no larger than a molecule—but can shear at sounds that are larger than life.

hearing loss research, deafness, hearing loss causesCilia function mechanically, fluttering back and forth in response to sound vibrations. The tug of the cilia creates tension in fine “tip links” that tether each cilium to its neighbor, causing them to pull open channels that allow ions to flow into the receptor cells. 

The cilia-tip link apparatus in the hair cell is a clever arrangement of spring-like and string-like protein molecules, yet their atomic structures and mechanical properties are not well known.

Now new work from the laboratories of David Corey, professor of neurobiology at Harvard Medical School and Howard Hughes Medical Institute investigator, and Rachelle Gaudet, associate professor of molecular and cellular biology at Harvard University's Faculty of Arts and Sciences, has discovered how the structure of a vital region of cadherin-23, one of two proteins that join to form each tip link, relates to . the hearing process and how we hear

“Our findings help explain a whole class of inherited deafness,” said Corey. “Many, many different mutations that cause inherited deafness are mutations specifically to the amino acids that bind the calcium. And these findings show how critical calcium ions, and the amino acid residues that bind them, are to the structure of this protein.”

The researchers then elected to test how mutations similar to those associated with inherited deafness might alter cadherin-23's structure and affinity for calcium ions.

“We had the three-dimensional structure of the wild type protein,” said Marcos Sotomayor, an HMS research fellow in neurobiology and co-lead author on the study, “and were able to obtain the structure of the mutated protein. With simulations, we could test both structures' elasticity and reactions to force.”

These findings, the researchers believe, offer insight that may one day better inform efforts to develop therapeutic interventions.

This research was funded by the National Institutes of Health, National Science Foundation, U.S. Department of Energy, Klingenstein Fellowship Award

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