期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 110, 期 6, 页码 2228-2233出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1222285110
关键词
channel; deafness; genomics; presbycusis
资金
- National Institutes of Health, National Institute on Deafness and Other Communication Disorders [R01 DC012546, R01 DC005575, R01 DC005989, R01 HL105631, R01 DC009645, R01 DC000139, R01 DC005641]
- Veterans' Administration
- Australia National Health and Medical Research Council [630618]
- New Zealand Marsden Fund
- Health Research Council and Deafness Research Foundation
- People's Republic of China National Natural Science Foundation [30528025]
Age-related hearing loss and noise-induced hearing loss are major causes of human morbidity. Here we used genetics and functional studies to showthat a shared cause of these disordersmay be loss of function of the ATP-gated P2X(2) receptor (ligand-gated ion channel, purinergic receptor 2) that is expressed in sensory and supporting cells of the cochlea. Genomic analysis of dominantly inherited, progressive sensorineural hearing loss DFNA41 in a six-generation kindred revealed a rare heterozygous allele, P2RX2 c.178G > T (p.V60L), at chr12: 133,196,029, which cosegregated with fully penetrant hearing loss in the index family, and also appeared in a second family with the same phenotype. The mutation was absent from more than 7,000 controls. P2RX2 p.V60L abolishes two hallmark features of P2X(2) receptors: ATP-evoked inward current response and ATP-stimulated macropore permeability, measured as loss of ATP-activated FM1-43 fluorescence labeling. Coexpression of mutant and WT P2X(2) receptor subunits significantly reduced ATP-activated membrane permeability. P2RX2-null mice developed severe progressive hearing loss, and their early exposure to continuous moderate noise led to high-frequency hearing loss as young adults. Similarly, among family members heterozygous for P2RX2 p.V60L, noise exposure exacerbated high-frequency hearing loss in young adulthood. Our results suggest that P2X(2) function is required for life-long normal hearing and for protection from exposure to noise.
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