{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T10:06:43Z","timestamp":1792145203669,"version":"4.4.0"},"reference-count":54,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,7,27]],"date-time":"2023-07-27T00:00:00Z","timestamp":1690416000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Neurosci."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>The pathogenic gene <jats:italic>CDH23<\/jats:italic> plays a pivotal role in tip links, which is indispensable for mechanoelectrical transduction in the hair cells. However, the underlying molecular mechanism and signal regulatory networks that influence deafness is still largely unknown.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In this study, a congenital deafness family, whole exome sequencing revealed a new mutation in the pathogenic gene <jats:italic>CDH23<\/jats:italic>, subsequently; the mutation has been validated using Sanger sequencing method. Then CRISPR\/Cas9 technology was employed to knockout zebrafish <jats:italic>cdh23<\/jats:italic> gene. Startle response experiment was used to compare with wide-type, the response to sound stimulation between wide-type and cdh23<jats:sup>\u2212\/\u2212<\/jats:sup>. To further illustrate the molecular mechanisms underlying congenital deafness, comparative transcriptomic profiling and multiple bioinformatics analyses were performed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The YO-PRO-1 assay result showed that in <jats:italic>cdh23<\/jats:italic> deficient embryos, the YO-PRO-1 signal in inner ear and lateral line neuromast hair cells were completely lost. Startle response experiment showed that compared with wide-type, the response to sound stimulation decreased significantly in <jats:italic>cdh23<\/jats:italic> mutant larvae. Comparative transcriptomic showed that the candidate genes such as <jats:italic>atp1b2b<\/jats:italic> and <jats:italic>myof<\/jats:italic> could affect hearing by regulating ATP production and purine metabolism in a synergetic way with <jats:italic>cdh23<\/jats:italic>. RT-qPCR results further confirmed the transcriptomics results. Further compensatory experiment showed that ATP treated cdh23<jats:sup>\u2212\/\u2212<\/jats:sup> embryos can partially recover the mutant phenotype.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>In conclusion, our study may shed light on deciphering the principal mechanism and provide a potential therapeutic method for congenital hearing loss under the condition of <jats:italic>CDH23<\/jats:italic> mutation.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fnmol.2023.1079529","type":"journal-article","created":{"date-parts":[[2023,7,28]],"date-time":"2023-07-28T03:34:55Z","timestamp":1690515295000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":13,"title":["cdh23 affects congenital hearing loss through regulating purine metabolism"],"prefix":"10.3389","volume":"16","author":[{"given":"Shu","family":"Yang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing-Lin","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-ping","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling-xiang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gang-hua","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tian","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-jing","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruo-sha","family":"Lai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong","family":"Tao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min-xin","family":"Guan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang-yi","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong-hui","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhong","family":"Deng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua-ping","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zi-an","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ding-hua","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,7,27]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"34794","DOI":"10.1074\/jbc.M402835200","article-title":"CLIC-5A functions as a Chloride Channel in vitro and associates with the cortical actin cytoskeleton in vitro and in vivo*","volume":"279","author":"Berryman","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1086\/316954","article-title":"Usher syndrome 1D and nonsyndromic autosomal recessive deafness DFNB12 are caused by allelic mutations of the novel cadherin-like gene CDH23","volume":"68","author":"Bork","year":"2001","journal-title":"Am. J. Hum. Genet."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1016\/j.cub.2017.12.044","article-title":"Nanoscale dynamism of actin enables secretory function in Cytolytic cells","volume":"28","author":"Carisey","year":"2018","journal-title":"Curr. Biol."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1111\/resp.13412","article-title":"Transcriptomics and single-cell RNA-sequencing","volume":"24","author":"Chambers","year":"2019","journal-title":"Respirology"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2019\/7365913","article-title":"Myoferlin, a membrane protein with emerging oncogenic roles","volume":"2019","author":"Dong","year":"2019","journal-title":"Biomed. Res. Int."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"667","DOI":"10.13201\/j.issn.1001-1781.2016.08.025","article-title":"Progress in the clinical application of gene detection technology of deafness","volume":"30","author":"Du","year":"2016","journal-title":"Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"e1005968","DOI":"10.1371\/journal.pcbi.1005968","article-title":"Reactome graph database: efficient access to complex pathway data","volume":"14","author":"Fabregat","year":"2018","journal-title":"PLoS Comput. Biol."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"134918","DOI":"10.1016\/j.neulet.2020.134918","article-title":"ATP depletion induced cochlear hair cells death through histone deacetylation in vitro","volume":"727","author":"Fan","year":"2020","journal-title":"Neurosci. Lett."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"446","DOI":"10.1016\/j.medcli.2012.02.014","article-title":"Genetics of congenital deafness","volume":"139","author":"Faundes","year":"2012","journal-title":"Med. Clin. (Barc.)"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"638","DOI":"10.1053\/j.gastro.2015.11.047","article-title":"Human Enteroids as a model of upper small intestinal ion transport physiology and pathophysiology","volume":"150","author":"Foulke-Abel","year":"2016","journal-title":"Gastroenterology"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"760422","DOI":"10.3389\/fncel.2021.760422","article-title":"Autophagy regulates the survival of hair cells and spiral ganglion neurons in cases of noise, ototoxic drug, and age-induced sensorineural hearing loss","volume":"15","author":"Guo","year":"2021","journal-title":"Front. Cell. Neurosci."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"4341","DOI":"10.1080\/15548627.2021.1916194","article-title":"FOXG1 promotes aging inner ear hair cell survival through activation of the autophagy pathway","volume":"17","author":"He","year":"2021","journal-title":"Autophagy"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1007\/s10162-003-4021-2","article-title":"Progressive hearing loss and increased susceptibility to noise-induced hearing loss in mice carrying a Cdh23 but not a Myo7a mutation","volume":"5","author":"Holme","year":"2004","journal-title":"J. Assoc. Res. Otolaryngol."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"628712","DOI":"10.3389\/fcell.2020.628712","article-title":"Using the zebrafish lateral line to understand the roles of mitochondria in sensorineural hearing loss","volume":"8","author":"Holmgren","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1007\/BF02740601","article-title":"Extracellular nucleotide signaling in the inner ear","volume":"16","author":"Housley","year":"1998","journal-title":"Mol. Neurobiol."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1038\/nprot.2008.211","article-title":"Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources","volume":"4","author":"Huang","year":"","journal-title":"Nat. Protoc."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1093\/nar\/gkn923","article-title":"Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists","volume":"37","author":"Huang","year":"","journal-title":"Nucleic Acids Res."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"D498","DOI":"10.1093\/nar\/gkz1031","article-title":"The reactome pathway knowledgebase","volume":"48","author":"Jassal","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1016\/j.ogc.2017.10.003","article-title":"Whole exome sequencing: applications in prenatal genetics","volume":"45","author":"Jelin","year":"2018","journal-title":"Obstet. Gynecol. Clin. N. Am."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1016\/j.devcel.2012.05.022","article-title":"Kinocilia mediate mechanosensitivity in developing zebrafish hair cells","volume":"23","author":"Kindt","year":"2012","journal-title":"Dev. Cell"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"114","DOI":"10.3389\/fcell.2018.00114","article-title":"Transmission disrupted: modeling auditory Synaptopathy in zebrafish","volume":"6","author":"Kindt","year":"2018","journal-title":"Front. Cell Dev. Biol."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"16094","DOI":"10.1038\/nrdp.2016.94","article-title":"Congenital hearing loss","volume":"3","author":"Korver","year":"2017","journal-title":"Nat. Rev. Dis. Primers."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"1385","DOI":"10.1016\/j.ijporl.2013.06.002","article-title":"Aetiology of congenital hearing loss: a cohort review of 569 subjects","volume":"77","author":"Lammens","year":"2013","journal-title":"Int. J. Pediatr. Otorhinolaryngol."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"1782","DOI":"10.1002\/eji.200535601","article-title":"Immunosuppressive role of semaphorin-3A on T cell proliferation is mediated by inhibition of actin cytoskeleton reorganization","volume":"36","author":"Lepelletier","year":"2006","journal-title":"Eur. J. Immunol."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"8898811","DOI":"10.1155\/2020\/8898811","article-title":"Alternative splicing of Cdh23 exon 68 is regulated by RBM24, RBM38, and PTBP1","volume":"2020","author":"Li","year":"2020","journal-title":"Neural Plast."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"4159","DOI":"10.1080\/15548627.2021.1905466","article-title":"PRDX1 activates autophagy via the PTEN-AKT signaling pathway to protect against cisplatin-induced spiral ganglion neuron damage","volume":"17","author":"Liu","year":"2021","journal-title":"Autophagy"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1093\/deafed\/enh017","article-title":"When parents are deaf versus hard of hearing: patterns of sign use and school placement of deaf and hard-of-hearing children","volume":"9","author":"Mitchell","year":"2004","journal-title":"J. Deaf. Stud. Deaf. Educ."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"272","DOI":"10.1038\/nature08250","article-title":"Targeted capture and massively parallel sequencing of 12 human exomes","volume":"461","author":"Ng","year":"2009","journal-title":"Nature"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1038\/nature08909","article-title":"Expansion of the eukaryotic proteome by alternative splicing","volume":"463","author":"Nilsen","year":"2010","journal-title":"Nature"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1038\/ng1226","article-title":"Association of cadherin 23 with polygenic inheritance and genetic modification of sensorineural hearing loss","volume":"35","author":"Noben-Trauth","year":"2003","journal-title":"Nat. Genet."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s10162-018-00711-1","article-title":"Water waves to sound waves: using zebrafish to explore hair cell biology","volume":"20","author":"Pickett","year":"2019","journal-title":"J. Assoc. Res. Otolaryngol."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1007\/978-981-10-7757-9_8","article-title":"The SarcoEndoplasmic reticulum calcium ATPase","volume":"87","author":"Primeau","year":"2018","journal-title":"Subcell. Biochem."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"1474","DOI":"10.3390\/genes11121474","article-title":"Identification of novel CDH23 variants causing moderate to profound progressive nonsyndromic hearing loss","volume":"11","author":"Ramzan","year":"2020","journal-title":"Genes"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1038\/ejhg.2014.83","article-title":"Progressive hearing loss and vestibular dysfunction caused by a homozygous nonsense mutation in CLIC5","volume":"23","author":"Seco","year":"2015","journal-title":"Eur. J. Hum. Genet."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"368","DOI":"10.1016\/j.semnephrol.2019.04.006","article-title":"Body fluid compartments, cell membrane ion transport, electrolyte concentrations, and Acid-Base balance","volume":"39","author":"Seifter","year":"2019","journal-title":"Semin. Nephrol."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"950","DOI":"10.1038\/nature02483","article-title":"Cadherin 23 is a component of the tip link in hair-cell stereocilia","volume":"428","author":"Siemens","year":"2004","journal-title":"Nature"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"6306","DOI":"10.1111\/j.1742-4658.2007.06145.x","article-title":"Functional reconstitution of mammalian 'chloride intracellular channels' CLIC1, CLIC4 and CLIC5 reveals differential regulation by cytoskeletal actin","volume":"274","author":"Singh","year":"2007","journal-title":"FEBS J."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"879","DOI":"10.1016\/S0140-6736(05)71047-3","article-title":"Sensorineural hearing loss in children","volume":"365","author":"Smith","year":"2005","journal-title":"Lancet"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"955","DOI":"10.1038\/nature02484","article-title":"Mutations in cadherin 23 affect tip links in zebrafish sensory hair cells","volume":"428","author":"Sollner","year":"2004","journal-title":"Nature"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"3172","DOI":"10.1039\/C8AN01852A","article-title":"Single cell transcriptomics: moving towards multi-omics","volume":"144","author":"Song","year":"2019","journal-title":"Analyst"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1038\/s41576-019-0150-2","article-title":"RNA sequencing: the teenage years","volume":"20","author":"Stark","year":"2019","journal-title":"Nat. Rev. Genet."},{"key":"ref42","doi-asserted-by":"publisher","first-page":"D607","DOI":"10.1093\/nar\/gky1131","article-title":"STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets","volume":"47","author":"Szklarczyk","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref43","doi-asserted-by":"publisher","first-page":"D362","DOI":"10.1093\/nar\/gkw937","article-title":"The STRING database in 2017: quality-controlled protein-protein association networks, made broadly accessible","volume":"45","author":"Szklarczyk","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref44","doi-asserted-by":"publisher","first-page":"1195","DOI":"10.1007\/s00431-019-03379-8","article-title":"The etiological evaluation of sensorineural hearing loss in children","volume":"178","author":"van Beeck Calkoen","year":"2019","journal-title":"Eur. J. Pediatr."},{"key":"ref45","doi-asserted-by":"publisher","first-page":"393","DOI":"10.3389\/fncel.2017.00393","article-title":"Inhibition of mitochondrial division attenuates cisplatin-induced toxicity in the Neuromast hair cells","volume":"11","author":"Vargo","year":"2017","journal-title":"Front. Cell. Neurosci."},{"key":"ref46","doi-asserted-by":"publisher","first-page":"701","DOI":"10.1016\/j.cell.2009.02.009","article-title":"The spliceosome: design principles of a dynamic RNP machine","volume":"136","author":"Wahl","year":"2009","journal-title":"Cells"},{"key":"ref47","doi-asserted-by":"publisher","first-page":"250","DOI":"10.1007\/s11684-016-0454-y","article-title":"Alternative splicing of inner-ear-expressed genes","volume":"10","author":"Wang","year":"2016","journal-title":"Front. Med."},{"key":"ref48","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2017\/8283075","article-title":"Evaluation of the hair cell regeneration in zebrafish larvae by measuring and quantifying the startle responses","volume":"2017","author":"Wang","year":"2017","journal-title":"Neural Plast."},{"key":"ref49","doi-asserted-by":"publisher","first-page":"F1492","DOI":"10.1152\/ajprenal.00030.2010","article-title":"CLIC5A, a component of the ezrin-podocalyxin complex in glomeruli, is a determinant of podocyte integrity","volume":"298","author":"Wegner","year":"2010","journal-title":"Am. J. Physiol. Renal Physiol."},{"key":"ref50","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1007\/s11684-017-0507-x","article-title":"Behavioral methods for the functional assessment of hair cells in zebrafish","volume":"11","author":"Yang","year":"2017","journal-title":"Front. Med."},{"key":"ref51","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1080\/15548627.2022.2062872","article-title":"Increased mitophagy protects cochlear hair cells from aminoglycoside-induced damage","volume":"19","author":"Zhang","year":"2023","journal-title":"Autophagy"},{"key":"ref52","doi-asserted-by":"publisher","first-page":"ddac270","DOI":"10.1093\/hmg\/ddac270","article-title":"Macrophage-mediated immune response aggravates hearing disfunction caused by the disorder of mitochondrial dynamics in cochlear hair cells","author":"Zhang","year":"","journal-title":"Hum. Mol. Genet."},{"key":"ref53","doi-asserted-by":"publisher","first-page":"e2203557","DOI":"10.1002\/advs.202203557","article-title":"Ti(3) C(2) T(x) MXene composite 3D hydrogel potentiates mTOR signaling to promote the generation of functional hair cells in cochlea organoids","volume":"9","author":"Zhang","year":"2022","journal-title":"Adv. Sci."},{"key":"ref54","doi-asserted-by":"publisher","first-page":"e1010232","DOI":"10.1371\/journal.pgen.1010232","article-title":"Dync1li1 is required for the survival of mammalian cochlear hair cells by regulating the transportation of autophagosomes","volume":"18","author":"Zhang","year":"","journal-title":"PLoS Genet."}],"container-title":["Frontiers in Molecular Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnmol.2023.1079529\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,28]],"date-time":"2023-07-28T03:35:02Z","timestamp":1690515302000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnmol.2023.1079529\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,27]]},"references-count":54,"alternative-id":["10.3389\/fnmol.2023.1079529"],"URL":"https:\/\/doi.org\/10.3389\/fnmol.2023.1079529","relation":{},"ISSN":["1662-5099"],"issn-type":[{"value":"1662-5099","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,7,27]]},"article-number":"1079529"}}