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Mutations in LOXHD1, an Evolutionarily Conserved Stereociliary Protein, Disrupt Hair Cell Function in Mice and Cause Progressive Hearing Loss in Humans |
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| Authors: | Nicolas Grillet Martin Schwander Michael S Hildebrand Anand Kolatkar Jennifer A Webster Hossein Najmabadi Dietrich Stephan Melanie Bahlo Lisa M Tarantino Richard JH Smith |
| Institution: | 1 Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037, USA 2 Department of Otolaryngology—Head and Neck Surgery, University of Iowa City, IA 55242, USA 3 Genome Institute of the Novartis Research Foundation, San Diego, CA 92121, USA 4 Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ 85004, USA 5 Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran 6 Department of Genetics, Boys Town National Research Hospital, Omaha, NE 68131, USA 7 Arizona Alzheimer's Consortium, Phoenix, AZ 85004, USA 8 Banner Alzheimer's Institute, Phoenix, AZ 85004, USA 9 Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville 3052 VIC, Australia 10 Department of Psychiatry, University of North Carolina, Chapel Hill, NC 27516, USA |
| Abstract: | Hearing loss is the most common form of sensory impairment in humans and is frequently progressive in nature. Here we link a previously uncharacterized gene to hearing impairment in mice and humans. We show that hearing loss in the ethylnitrosourea (ENU)-induced samba mouse line is caused by a mutation in Loxhd1. LOXHD1 consists entirely of PLAT (polycystin/lipoxygenase/α-toxin) domains and is expressed along the membrane of mature hair cell stereocilia. Stereociliary development is unaffected in samba mice, but hair cell function is perturbed and hair cells eventually degenerate. Based on the studies in mice, we screened DNA from human families segregating deafness and identified a mutation in LOXHD1, which causes DFNB77, a progressive form of autosomal-recessive nonsyndromic hearing loss (ARNSHL). LOXHD1, MYO3a, and PJVK are the only human genes to date linked to progressive ARNSHL. These three genes are required for hair cell function, suggesting that age-dependent hair cell failure is a common mechanism for progressive ARNSHL. |
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