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Proteins That Help the Ear Detect Sound

Proteins That Help the Ear Detect Sound

Stereocilia.

Scanning electron microscopy shows the stair-step pattern of stereocilia.
Credit: B. Kachar, NIDCD

Background: Many of the tiny structures important for hearing are built from proteins or require proteins to function. In 2005, NIDCD-supported scientists made some critical discoveries about how proteins help the ear detect sound.

Advances: Stereocilia on a single auditory hair cell are bundled together in a staircase shape that is needed for normal hearing and balance. By studying what goes wrong in mice that inherit defective genes, NIDCD scientists have discovered how two proteins work together to build normal stereocilia. The MyoXVa (myosin 15a) protein binds and transports the whirlin protein from the main part of the hair cell (the cell body) out to the tips of developing stereocilia. The stereocilia “grow” by adding proteins to their ends. When mice inherit defective genes for MyoXVa or whirlin proteins, their stereocilia do not develop into the normal staircase pattern, and the mice are deaf. However, gene therapy that reintroduces normal copies of the mutant genes can “rescue” normal stereocilia formation.

Individuals who inherit mutated copies of another myosin gene, MyoVIIa, are deaf and have balance problems, which constitute a syndrome called Usher Type 1B. Until recently, scientists did not know how the mutation caused these problems. NIDCD-supported scientists identified the fruit fly equivalent of MyoVIIa, known as crinkled. Flies with mutant copies of crinkled suffer symptoms similar to human Usher 1B Syndrome. The fruit fly equivalents of hair cells in the mutants develop in a disorganized manner and cannot detect sound. Scientists can now study this insect model of Usher 1B Syndrome to help them understand the human disorder.

Finally, NIDCD-supported scientists have identified yet another protein that is critical to our ability to detect sound. A fine filament called a tip link connects the tips of adjacent hair cell stereocilia, and tip links pull on channels in the hair cell membranes to open them. Charged ions rushing through these channels change the voltage inside the cells and set off an electrical current (nerve impulse) that travels to the brain and is detected as sound. Now NIDCD-supported scientists have found the protein that forms the hair cell channels. TRPA1 is made by hair cells, is located in the tips of stereocilia, and is necessary for hair cells to respond to sound. It also forms an unusual extended elastic chain that may pull and open the channel. When the scientists blocked TRPA1 formation in animals, their hair cells were unable to conduct electrical current, suggesting that ions could not enter the stereocilia.

Implications: These studies help scientists understand how genes and their associated proteins function in normal ears to help detect sound. This detailed understanding at the molecular level may help scientists develop gene therapies for some forms of hereditary deafness in humans.

Citations: Corey DP, Garcia-Anoveros J, Holt JR, Kwan KY, Lin SY, Vollrath MA, Amalfitano A, Cheung EL, Derfler BH, Duggan A, Geleoc GS, Gray PA, Hoffman MP, Rehm HL, Tamasauskas D, Zhang DS, TRPA1 is a candidate for the mechanosensitive transduction channel of vertebrate hair cells. Nature 432: 723-30, 2004

Belyantseva IA, Boger ET, Naz S, Frolenkov GI, Sellers JR, Ahmed ZM, Griffith AJ, Friedman TB, Myosin-XVa is required for tip localization of whirlin and differential elongation of hair-cell stereocilia. Nat Cell Biol 7: 148-56, 2005.

Todi SV, Franke JD, Kiehart DP, Eberl DF, Myosin VIIA defects, which underlie the Usher 1B syndrome in humans, lead to deafness in Drosophila. Curr Biol 15: 862-868, 2005.

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