Mutation of the ATP-gated P2X(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 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.
Department of Otolaryngology, University of Miami School of Medicine, Miami, FL 33136, USA.
Denise
D
Yan
Yan
Y
Zhu
Tom
T
Walsh
Dinghua
D
Xie
Huijun
H
Yuan
Asli
A
Sirmaci
Taro
T
Fujikawa
Ann Chi Yan
AC
Wong
Tze L
TL
Loh
Lilin
L
Du
M'hamed
M
Grati
Srdjan M
SM
Vlajkovic
Susan
S
Blanton
Allen F
AF
Ryan
Zheng-Yi
ZY
Chen
Peter R
PR
Thorne
Bechara
B
Kachar
Mustafa
M
Tekin
Hong-Bo
HB
Zhao
Gary D
GD
Housley
Mary-Claire
MC
King
Xue Z
XZ
Liu
D000255:Adenosine Triphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D004195:Disease Models, Animal; D005072:Evoked Potentials, Auditory; D005260:Female; D005799:Genes, Dominant; D006317:Hearing Loss, Noise-Induced / Q000209:etiology / Q000235:genetics* / Q000503:physiopathology; D006319:Hearing Loss, Sensorineural / Q000209:etiology / Q000235:genetics* / Q000503:physiopathology; D006579:Heterozygote; D006801:Humans; D015640:Ion Channel Gating; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D019683:Penetrance; D058476:Receptors, Purinergic P2X2 / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D017386:Sequence Homology, Amino Acid; D055815:Young Adult
D058476:Receptors, Purinergic P2X2; D000255:Adenosine Triphosphate