Mutation of the ATP-gated P2X2 receptor leads to progressive hearing loss and increased susceptibility to noise

Denise Yan, Yan Zhu, Tom Walsh, Dinghua Xie, Huijun Yuan, Asli Sirmaci, Taro Fujikawa, Ann Chi Yan Wong, Tze L. Loh, Lilin Du, M'hamed Grati, Srdjan M. Vlajkovic, Susan Blanton, Allen F. Ryan, Zheng Yi Chen, Peter R. Thorne, Bechara Kachar, Mustafa Tekin, Hong Bo Zhao, Gary D. HousleyMary Claire King, Xue Z. Liu

Research output: Contribution to journalArticlepeer-review

108 Scopus citations


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. Themutation was absent frommore 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.

Original languageEnglish
Pages (from-to)2228-2233
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number6
StatePublished - Feb 5 2013


  • Channel
  • Deafness
  • Genomics
  • Presbycusis

ASJC Scopus subject areas

  • General


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