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

Proc Natl Acad Sci U S A. 2013 Feb 5;110(6):2228-33. doi: 10.1073/pnas.1222285110. Epub 2013 Jan 23.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Amino Acid Sequence
  • Animals
  • Disease Models, Animal
  • Evoked Potentials, Auditory
  • Female
  • Genes, Dominant
  • Hearing Loss, Noise-Induced / etiology
  • Hearing Loss, Noise-Induced / genetics*
  • Hearing Loss, Noise-Induced / physiopathology
  • Hearing Loss, Sensorineural / etiology
  • Hearing Loss, Sensorineural / genetics*
  • Hearing Loss, Sensorineural / physiopathology
  • Heterozygote
  • Humans
  • Ion Channel Gating
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Molecular Sequence Data
  • Mutation, Missense*
  • Pedigree
  • Penetrance
  • Receptors, Purinergic P2X2 / deficiency
  • Receptors, Purinergic P2X2 / genetics*
  • Receptors, Purinergic P2X2 / physiology
  • Sequence Homology, Amino Acid
  • Young Adult


  • Receptors, Purinergic P2X2
  • Adenosine Triphosphate

Supplementary concepts

  • Deafness, Autosomal Dominant 41