Mutation of the ATP-gated P2X^sub 2^ receptor leads to progressive hearing loss and increased susceptibility to noise

Age-related hearing loss and noise-induced hearing loss are major causes of human morbidity. Here we used genetics and functional studies to show that a shared cause of these disorders may be loss of function of the ATP-gated P2X2 receptor (ligand-gated ion channel, purinergic receptor 2) that is ex...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2013-02, Vol.110 (6), p.2228
Main Authors: Yan, Denise, Zhu, Yan, Walsh, Tom, Xie, Dinghua, Yuan, Huijun, Sirmaci, Asli, Fujikawa, Taro, Wong, Ann Chi Yan, Loh, Tze L, Du, Lilin, Grati, M'hamed, Vlajkovic, Srdjan M, Blanton, Susan, Ryan, Allen F, Chen, Zheng-Yi, Thorne, Peter R, Kachar, Bechara, Tekin, Mustafa, Zhao, Hong-Bo, Housley, Gary D, King, Mary-Claire, Liu, Xue Z
Format: Article
Language:English
Subjects:
Adenosine triphosphatase
Deafness
Genomics
Morbidity
Mutation
Noise
Permeability
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Summary:Age-related hearing loss and noise-induced hearing loss are major causes of human morbidity. Here we used genetics and functional studies to show that a shared cause of these disorders may be loss of function of the ATP-gated P2X2 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 P2X2 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 P2X2 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 P2X2 function is required for life-long normal hearing and for protection from exposure to noise. [PUBLICATION ABSTRACT]
ISSN:0027-8424
1091-6490