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The Skaggs Institute
for Chemical Biology

Scientific Report 2007

Auditory Perception and Hearing Impairment: From Mouse Models to Human Genetic Disease

U. Müller, C. Barros, R. Belvindrah, F. Conti, S. Franco, N. Grillet, S. Harkins-Perry, P. Kazmierczak, I. Martinez-Garay, Y. Pavlova, R. Radakovits, C. Ramos, A. Reynolds, A. Sczaniecka, M. Schwander, S. Webb, W. Xiong

Sense organs convert signals such as light and sound into electrical impulses that are processed by the nervous system to create an internal representation of our surroundings and to elicit appropriate behavioral responses. Of all the sensory systems in humans, the auditory system is the least well understood at the molecular level. We identify and study genes that control the function of the auditory sense organ of mammals. We also analyze the mechanisms that establish neuronal connections between the auditory sense organs and the cerebral cortex and the formation of cell layers and neuronal circuits within the cortex.

Mechanoelectrical Transduction and Hearing: Human Genetics

The ability to perceive sound is critically dependent on mechanoelectical transduction (MET), the conversion of mechanical force into electrical signals. The auditory mechanoreceptor cells in mammals are the hair cells of the cochlea. The architectural features of the cochlea and the properties of the hair cells are essential for encoding time-variant frequency components of sound as spatiotemporal arrays of neural discharge that provide the sense of hearing. The mechanically sensitive organelle of a hair cell is the hair bundle, which consists of dozens of stereocilia that project from the apical cell surface. MET channels are localized close to the tips of stereocilia. Tip-links, extracellular filaments that connect the tips of neighboring stereocilia and are visible by electron microscopy, are thought to transmit sound-induced tension force onto the MET channel. The molecular identity of most components of the MET complex is still unknown.

To identify genes that control hair cell function, such as the MET channel and the tip-links, we use genetic approaches. Approximately 1 in 1000 children is born deaf, and a large part of the human population experiences age-related hearing loss. Many forms of hearing loss are of genetic origin, and mutations in more than 400 genes cause deafness. Some of the affected genes have been identified and may encode components of the MET complex in hair cells. Two of the genes linked to deafness encode cadherin 23 and protocadherin 15, members of the cadherin superfamily of cell adhesion molecules. Both genes are expressed in hair cells, and our recent studies showed that cadherin 23 and protocadherin 15 interact to form tip-link filaments. Our findings defined the first components of the MET complex in hair cells at the molecular level and provide tools for identifying additional components of the MET complex that likely interact with cadherin 23 and protocadherin 15, such as mechanically gated ion channels.

Intriguingly, some of the mutations in the genes for cadherin 23 and protocadherin 15 that cause deafness in humans disrupt interactions between the 2 proteins. Others leave interactions intact and likely change the mechanical properties of the tip-link and affect the MET process. We classify these diseases as MET diseases.

The Molecular Pathogenesis of Deafness: Animal Models for the Human Disease

Deafness has a profound effect on the quality of life of the affected individuals, yet few promising therapeutic approaches exist to help these individuals. To identify genes that control auditory perception and to provide animal models for the human disease, we carried out a genetic screen in mice. Using N-ethyl-N-nitrosourea, we introduced point mutations in the germ line of mice. Using phenotypic screens, we identified 19 mouse lines in which the mice inherit hearing defects as recessive traits. We have mapped many of the mutations to chromosomal intervals and have used DNA sequencing to identify mutations in single genes that cause some of the hearing defects.

All the genes that we have identified so far are expressed in hair cells. Some of the genes encode proteins with known functions, such as myosin motor proteins. Others belong to entirely new gene families that have not been studied before. Several of the genes identified in our screen had already been linked to deafness, but we also identified mutations in genes that had not. One of these genes encodes the protein pejvakin. Our studies indicate that pejvakin is expressed in hair cells and is required for their function. We have screened human families with deafness for mutations in the pejvakin gene and have identified a mutation in an Iranian family that is inherited as a recessive trait.

Our studies show that genetic screens in mice are powerful not only for identifying genes that control the function of hair cells but also for linking genes to disease in humans. In future studies, we will define the structure and function of the normal and pathogenic variants of the proteins to gain insights into disease mechanisms at the cellular, molecular, and anatomic levels.


Herr, D., Grillet, N., Schwander, M., Rivera, R., Müller, U., Chun, J. Sphingosine 1-phosphate signaling is required for maintenance of hair cells mainly via activation of S1P2. J. Neurosci. 27:1474, 2007.

Kazmierczak, P., Sakaguchi, H., Tokita, J., Wilson-Kubalek, E.M., Milligan, R.A., Müller, U., Kachar B. Cadherin 23 and protocadherin 15 interact to form tip-link filaments in sensory hair cells. Nature 449:87, 2007.

Schwander, M., Sczaniecka, A., Grillet, N., Bailey, J.S., Avenarius, M., Najmabadi, H., Steffy, B.M., Federe, G.C., Lagler, E.A., Banan, R., Hice, R., Grabowski-Boase, L., Keithley, E.M., Ryan, A.F., Housley, G.D., Wiltshire, T., Smith, R.J.H., Tarantino, L.M., Müller, U. A forward genetics screen in mice identifies recessive deafness traits and reveals that pejvakin is essential for outer hair cell function.
J. Neurosci. 27:2163, 2007.

Senften, M., Schwander, M., Kazmierczak, P, Lillo, C., Shin, J.B., Hasson, T., Géléoc, G.S.G., Gillespie, P.G., Williams, D., Holt, J.R., Müller, U. Physical and functional interaction between protocadherin 15 and myosin VIIa in mechanosensory hair cells. J. Neurosci. 26:2060, 2006.


Ulrich Müller, Ph.D.

Müller Web Site