{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T11:17:32Z","timestamp":1792495052271,"version":"4.5.0"},"reference-count":36,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2021,3,31]],"date-time":"2021-03-31T00:00:00Z","timestamp":1617148800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["R01DC012115"],"award-info":[{"award-number":["R01DC012115"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["R01DC005575"],"award-info":[{"award-number":["R01DC005575"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,5,31]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>P2RX2 encodes the P2X2 receptor, which is an adenosine triphosphate (ATP) gated (purinoreceptor) ion channel. P2RX2 c. 178G\u2009&amp;gt;\u2009T (p.V60L) mutation was previously identified in two unrelated Chinese families, as the cause of human DFNA41, a form of dominant, early-onset and progressive sensorineural hearing loss. We generated and characterized a knock-in mouse model based on human p.V60L mutation that recapitulates the human phenotype. Heterozygous KI mice started to exhibit hearing loss at 21-day-old and progressed to deafness by 6-month-old. Vestibular dysfunction was also observed in mutant mice. Abnormal morphology of the inner hair cells and ribbon synapses was progressively observed in KI animals suggesting that P2rx2 plays a role in the membrane spatial location of the ribbon synapses. These results suggest that P2rx2 is essential for acoustic information transfer, which can be the molecular mechanism related to hearing loss.<\/jats:p>","DOI":"10.1093\/hmg\/ddab077","type":"journal-article","created":{"date-parts":[[2021,3,30]],"date-time":"2021-03-30T19:12:45Z","timestamp":1617131565000},"page":"985-995","source":"Crossref","is-referenced-by-count":10,"title":["Generation and characterization of a <i>P2rx2<\/i> V60L mouse model for DFNA41"],"prefix":"10.1093","volume":"30","author":[{"given":"Xiaoya","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, FL 33136, USA"},{"name":"Department of Otolaryngology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clemer","family":"Abad","sequence":"additional","affiliation":[{"name":"John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng-yi","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology and Program in Neuroscience, Harvard Medical School and Eaton Peabody Laboratory, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts 02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan I","family":"Young","sequence":"additional","affiliation":[{"name":"John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136, USA"},{"name":"Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Channabasavaiah B","family":"Gurumurthy","sequence":"additional","affiliation":[{"name":"Mouse Genome Engineering Core Facility, Vice Chancellor for Research Office, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherina","family":"Walz","sequence":"additional","affiliation":[{"name":"John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136, USA"},{"name":"Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue Zhong","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, FL 33136, USA"},{"name":"Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,3,31]]},"reference":[{"key":"2021070819094445900_ref1","doi-asserted-by":"crossref","first-page":"2151","DOI":"10.1056\/NEJMra050700","article-title":"Newborn hearing screening--a silent revolution","volume":"354","author":"Morton","year":"2006","journal-title":"N. Engl. J. 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Physiol."},{"key":"2021070819094445900_ref10","first-page":"11","article-title":"Mouse genome editing using the CRISPR\/Cas system","volume":"83","author":"Harms","year":"2014","journal-title":"Curr. Protoc. Hum.Genet"},{"key":"2021070819094445900_ref11","doi-asserted-by":"crossref","DOI":"10.1186\/s13059-017-1220-4","article-title":"Easi-CRISPR: a robust method for one-step generation of mice carrying conditional and insertion alleles using long ssDNA donors and CRISPR ribonucleoproteins","volume":"18","author":"Quadros","year":"2017","journal-title":"Genome Biol."},{"key":"2021070819094445900_ref12","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1038\/nprot.2017.153","article-title":"Easi-CRISPR for creating knock-in and conditional knockout mouse models using long ssDNA donors","volume":"13","author":"Miura","year":"2018","journal-title":"Nat. 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Res."},{"key":"2021070819094445900_ref23","doi-asserted-by":"crossref","first-page":"3989201","DOI":"10.1155\/2018\/3989201","article-title":"N-methyl-D-aspartate receptors involvement in the gentamicin-induced hearing loss and pathological changes of ribbon synapse in the mouse Cochlear inner hair cells","volume":"2018","author":"Hong","year":"2018","journal-title":"Neural Plast."},{"key":"2021070819094445900_ref24","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1038\/nn.2803","article-title":"Position-dependent patterning of spontaneous action potentials in immature cochlear inner hair cells","volume":"14","author":"Johnson","year":"2011","journal-title":"Nat. Neurosci."},{"key":"2021070819094445900_ref25","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1007\/s00232-005-0854-4","article-title":"Structure and function of the hair cell ribbon synapse","volume":"209","author":"Nouvian","year":"2006","journal-title":"J. Membr. 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