Details

Autor(en) / Beteiligte

• 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.

Titel

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

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2013-02, Vol.110 (6), p.2228-2233

Ort / Verlag

National Academy of Sciences

Erscheinungsjahr

2013

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• 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 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.