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Mutation of the ATP-Gated P2X2 Receptor Leads to Progressive Hearing Loss and Increased Susceptibility to Noise

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Mutation of the ATP-Gated P2X2 Receptor Leads to Progressive Hearing Loss and Increased Susceptibility to Noise Mutation of the ATP-gated P2X2 receptor leads to progressive hearing loss and increased susceptibility to noise Denise Yana, Yan Zhub, Tom Walshc, Dinghua Xied, Huijun Yuane, Asli Sirmacif, Taro Fujikawag, Ann Chi Yan Wongh, Tze L. Lohh, Lilin Dua,M’hamed Gratia,g, Srdjan M. Vlajkovici, Susan Blantonf, Allen F. Ryanj, Zheng-Yi Chenk, Peter R. Thornei, Bechara Kacharg, Mustafa Tekinf, Hong-Bo Zhaob, Gary D. Housleyh, Mary-Claire Kingc,1, and Xue Z. Liua,d,f,1 aDepartment of Otolaryngology, University of Miami School of Medicine, Miami, FL 33136; bDepartment of Otolaryngology, University of Kentucky Medical Center, Lexington, KY 40536; cDepartment of Medicine and Department of Genome Sciences, University of Washington, Seattle, WA 98195; dDepartment of Otolaryngology and Head-Neck Surgery, Second Xiangya Hospital of Central South University, Changsha 410011, China; eInstitute of Otolaryngology, Chinese PLA General Hospital, Beijing 100853, China; fDepartment of Human Genetics, University of Miami School of Medicine, Miami, FL 33136; gLaboratory of Cell Structure and Dynamics, Section on Structural Cell Biology, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20892; hTranslational Neuroscience Facility and Department of Physiology, School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia; iDepartment of Physiology and Centre for Brain Research, School of Medical Sciences and Section of Audiology, School of Population Health, University of Auckland, Auckland, New Zealand; jDepartments of Otolaryngology and Neurosciences, University of California at San Diego, La Jolla, CA 92093; and kEaton-Peabody Laboratory, Department of Otology and Laryngology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114 Contributed by Mary-Claire King, December 20, 2012 (sent for review November 28, 2012) Age-related hearing loss and noise-induced hearing loss are major assembles as a trimer to form a channel gated by extracellular causes of human morbidity. Here we used genetics and functional ATP. P2X2 receptors mediate a variety of cellular responses, in- studies to show that a shared cause of these disorders may be loss of cluding excitatory postsynaptic responses in sensory neurons (10, function of the ATP-gated P2X2 receptor (ligand-gated ion channel, 11). In the inner ear, P2X2 receptors are thought to regulate GENETICS purinergic receptor 2) that is expressed in sensory and supporting sound transduction and auditory neurotransmission (12–14), outer hair cell electromotility (15, 16), inner ear gap junctions cells of the cochlea. Genomic analysis of dominantly inherited, pro- + gressive sensorineural hearing loss DFNA41 in a six-generation kin- (17), and K recycling (17, 18). We explored the effect of the dred revealed a rare heterozygous allele, P2RX2 c.178G > T (p.V60L), inherited mutation in P2RX2 on function of the P2X2 receptors at chr12:133,196,029, which cosegregated with fully penetrant hear- and the consequences of loss of function of these ATP-gated ing loss in the index family, and also appeared in a second family channels on progressive and noise-induced hearing loss. with the same phenotype. The mutation was absent from more than Results 7,000 controls. P2RX2 p.V60L abolishes two hallmark features of Discovery of P2RX2 as Responsible for Progressive Hearing Loss P2X2 receptors: ATP-evoked inward current response and ATP-stim- DFNA41. DFNA41 is an autosomal dominant, progressive, senso- ulated macropore permeability, measured as loss of ATP-activated fi FM1-43 fluorescence labeling. Coexpression of mutant and WT rineural hearing loss de ned in a six-generation kindred living in Sichuan, China (19). Audiologic evaluation of family members P2X2 receptor subunits significantly reduced ATP-activated mem- brane permeability. P2RX2-null mice developed severe progressive revealed bilateral and symmetrical sensorineural hearing loss, with age at onset ranging from 12 y to 20 y, generally accompanied by hearing loss, and their early exposure to continuous moderate noise high-frequency tinnitus. Hearing loss was progressive and ulti- led to high-frequency hearing loss as young adults. Similarly, among mately involved all frequencies. The gene responsible for hearing family members heterozygous for P2RX2 p.V60L, noise exposure loss in the family was localized by linkage analysis to the region exacerbated high-frequency hearing loss in young adulthood. Our between D12S1609 and 12qter (19), but Sanger sequencing of eight results suggest that P2X2 function is required for life-long normal genes in this interval did not identify the responsible gene (20). hearing and for protection from exposure to noise. The DFNA41 linkage interval corresponds to the 4.80-MB ge- nomic region chr12:129,051,849–133,851,895 (hg19) and includes channel | deafness | genomics | presbycusis at least 34 genes. To identify the gene responsible for hearing loss in the family, we captured and sequenced all 427 coding exons, earing loss is a socially and economically important cause of noncoding exons, and documented regulatory regions in the linked Hhuman morbidity, affecting 538 million people worldwide, interval from genomic DNA of three affected family members. including 36 million people in the United States (1, 2). Hearing Using a pipeline for variant discovery from massively parallel loss is often related to inherited genetic lesions, with 60 of the sequences (21), we identified all variants in the targeted region. In critical genes identified and more than 100 others mapped the 4.80-MB region, the three affected individuals shared 216 (http://hereditaryhearingloss.org). The identification of genes variants, of which 206 were common polymorphisms also present in for inherited forms of hearing loss that progress with age is par- ticularly important for understanding age-related hearing loss, or presbycusis, which affects more than 40% of people over age 65 y Author contributions: D.Y., T.W., M.G., B.K., M.T., H.-B.Z., G.D.H., M.-C.K., and X.Z.L. de- (3). Age-related hearing loss is influenced both by genetics and by signed research; D.Y., Y.Z., T.W., A.S., T.F., A.C.Y.W., T.L.L., L.D., M.G., S.M.V., S.B., H.-B.Z., environmental factors, including exposure to noise in the work- G.D.H., M.-C.K., and X.Z.L. performed research; D.X., H.Y., A.F.R., Z.-Y.C., B.K., H.-B.Z., – G.D.H., and X.Z.L. contributed new reagents/analytic tools; D.Y., Y.Z., T.W., A.S., T.F., place, in the environment, or recreationally (4 7). Noise-induced A.C.Y.W., T.L.L., L.D., M.G., S.M.V., S.B., P.R.T., M.T., H.-B.Z., G.D.H., M.-C.K., and X.Z.L. hearing loss is also influenced by genetic factors (8, 9), although analyzed data; and M.G., S.M.V., P.R.T., B.K., M.T., H.-B.Z., G.D.H., M.-C.K., and X.Z.L. causal genes have not heretofore been identified. An important wrote the paper. focus of current hearing research is on the biological mechanisms The authors declare no conflict of interest. underlying age-related and noise-induced hearing loss. 1To whom correspondence should be addressed. E-mail: [email protected] or Here we report the identification of a mutation in the P2RX2 [email protected]. gene as the cause of dominantly inherited, progressive hearing This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. loss in two families. P2RX2 encodes the P2X2 receptor, which 1073/pnas.1222285110/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1222285110 PNAS Early Edition | 1of6 Downloaded by guest on October 2, 2021 multiple other family members and unrelated persons. The 10 rare of China than the DFNA41 family. The two families were not aware variants included 5 intronic variants, 3 intergenic variants, 1 syn- of any relationship between them. All affected individuals in the onymous coding sequence change, and 1 nonsynonymous change. second family had bilateral moderate to severe progressive senso- Only the nonsynonymous change altered a conserved nucleotide rineural hearing loss with onset in the second decade, similar to site: chr12:133,196,029 G > T (hg19), corresponding to P2RX2 affected members of the original DFNA41 family. A computed c.178G > T (p.V60L NM_174873). This variant was confirmed tomography scan of one affected family member revealed normal by Sanger sequencing (Fig. 1A). The residue is conserved as temporal bones. Middle ear status was normal, and clinical exami- valine in all sequenced vertebrates, from zebrafish to mammals nations revealed no other abnormalities. The mutation was absent (Fig. 1B). The mutation has been predicted to affect protein from 7,000 controls, including 4,300 persons of European ancestry, function (22). 2,200 persons of African-American ancestry (evs.gs.washington.edu/ In the family defining DFNA41, P2RX2 c.178G > T (p.V60L) EVS/), and 500 persons of Chinese ancestry. Thus, the P2RX2 cosegregated perfectly with hearing loss, with an LOD score of 13.3, c.178G > T allele has an estimated frequency of <0.001 in the corresponding to odds of 1013:1 in favor of linkage (Fig. 1C). Pen- Chinese population and of <0.0001 in a mixed-ancestry population. etrance of the phenotype among heterozygous mutation carriers Among the DFNA41 family members heterozygous for P2RX2 was 100%. Sequencing of the entire P2RX2 coding sequence in 65 p.V60L, hearing loss progressed with age. Hearing loss was first other families with autosomal dominant nonsyndromic sensori- detected in the second decade of life and was severe (60–70 dB) neural hearing loss yielded one other family, also Chinese, carrying by age 20 y, with little further progression thereafter (Fig. 1E). P2RX2 c.178G > T (Fig. 1D). This family lives in a different region Some family members exhibited elevated thresholds at one or Fig.
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