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The Journal of Neuroscience, February 28, 2007, 27(9):2163-2175; doi:10.1523/JNEUROSCI.4975-06.2007

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Neurobiology of Disease
A Forward Genetics Screen in Mice Identifies Recessive Deafness Traits and Reveals That Pejvakin Is Essential for Outer Hair Cell Function

Martin Schwander,¹ Anna Sczaniecka,¹ Nicolas Grillet,¹ Janice S. Bailey,² Matthew Avenarius,³ Hossein Najmabadi,⁴ Brian M. Steffy,² Glenn C. Federe,² Erica A. Lagler,² Raheleh Banan,¹ Rudy Hice,² Laura Grabowski-Boase,² Elisabeth M. Keithley,⁵ Allen F. Ryan,⁵ Gary D. Housley,⁶ Tim Wiltshire,² Richard J. H. Smith,³ Lisa M. Tarantino,² and Ulrich Müller¹

¹Department of Cell Biology, Institute for Childhood and Neglected Disease, The Scripps Research Institute, La Jolla, California 92037, ²Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, ³Department of Otolaryngology and the Interdepartmental Ph.D. Genetic Program, The University of Iowa, Iowa City, Iowa 52242, ⁴Genetic Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran, ⁵Departments of Surgery and Neurosciences, University of California, San Diego School of Medicine and Veterans Affairs Medical Center, La Jolla, California 92093, and ⁶Department of Physiology, University of Auckland, Auckland, New Zealand

Correspondence should be addressed to either of the following: Dr. Ulrich Müller, The Scripps Research Institute, Mail Drop ICND222, 10550 North Torrey Pines Road, La Jolla, CA 92037, Email: umueller{at}scripps.edu; or Dr. Lisa M. Tarantino, Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, Email: ltaranti{at}gnf.org

Deafness is the most common form of sensory impairment in the human population and is frequently caused by recessive mutations. To obtain animal models for recessive forms of deafness and to identify genes that control the development and function of the auditory sense organs, we performed a forward genetics screen in mice. We identified 13 mouse lines with defects in auditory function and six lines with auditory and vestibular defects. We mapped several of the affected genetic loci and identified point mutations in four genes. Interestingly, all identified genes are expressed in mechanosensory hair cells and required for their function. One mutation maps to the pejvakin gene, which encodes a new member of the gasdermin protein family. Previous studies have described two missense mutations in the human pejvakin gene that cause nonsyndromic recessive deafness (DFNB59) by affecting the function of auditory neurons. In contrast, the pejvakin allele described here introduces a premature stop codon, causes outer hair cell defects, and leads to progressive hearing loss. We also identified a novel allele of the human pejvakin gene in an Iranian pedigree that is afflicted with progressive hearing loss. Our findings suggest that the mechanisms of pathogenesis associated with pejvakin mutations are more diverse than previously appreciated. More generally, our findings demonstrate that recessive screens in mice are powerful tools for identifying genes that control the development and function of mechanosensory hair cells and cause deafness in humans, as well as generating animal models for disease.

Key words: ENU; inner ear; hearing loss; gasdermin; deafness; genetics

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Received Nov. 15, 2006; revised Jan. 9, 2007; accepted Jan. 11, 2007.

Correspondence should be addressed to either of the following: Dr. Ulrich Müller, The Scripps Research Institute, Mail Drop ICND222, 10550 North Torrey Pines Road, La Jolla, CA 92037, Email: umueller{at}scripps.edu; or Dr. Lisa M. Tarantino, Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, Email: ltaranti{at}gnf.org

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