{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T07:19:22Z","timestamp":1787901562867,"version":"build-2784847793"},"reference-count":59,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T00:00:00Z","timestamp":1785715200000},"content-version":"vor","delay-in-days":2,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82201169"],"award-info":[{"award-number":["82201169"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32270715"],"award-info":[{"award-number":["32270715"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82471090"],"award-info":[{"award-number":["82471090"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["2022M711952"],"award-info":[{"award-number":["2022M711952"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["2022TQ0198"],"award-info":[{"award-number":["2022TQ0198"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007129","name":"Natural Science Foundation of Shandong Province","doi-asserted-by":"publisher","award":["2601010520249H"],"award-info":[{"award-number":["2601010520249H"]}],"id":[{"id":"10.13039\/501100007129","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CNS Neurosci Ther"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Usher syndrome 3A (USH3A), caused by mutations in the\n                      <jats:italic>CLRN1<\/jats:italic>\n                      gene, leads to retinitis pigmentosa and sensorineural hearing loss. While\n                      <jats:italic>CLRN1<\/jats:italic>\n                      's role in inner ear pathology is established, its contribution to retinal degeneration remains poorly understood.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Retinal organoids derived from a USH3A patient were analyzed using single\u2010cell RNA sequencing and multi\u2010electrode array recording.\n                      <jats:italic>CLRN1<\/jats:italic>\n                      expression was mapped in human fetal retina and organoids. We assessed the structural, transcriptional, and functional impact of\n                      <jats:italic>CLRN1<\/jats:italic>\n                      variants on M\u00fcller cells and photoreceptors, and evaluated idebenone as a potential targeted therapy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      <jats:italic>CLRN1<\/jats:italic>\n                      was specifically expressed in M\u00fcller cells.\n                      <jats:italic>CLRN1<\/jats:italic>\n                      variants induced severe retinal degeneration, characterized by outer nuclear layer thinning, impaired photoreceptor gene expression, activated apoptosis, and diminished electrophysiological function. Mechanistically, these variants caused mitochondrial dysfunction in M\u00fcller cells, which triggered secondary mitochondrial impairment, oxidative stress, and apoptosis in photoreceptors. Idebenone treatment partially rescued these deficits.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      <jats:italic>CLRN1<\/jats:italic>\n                      \u2010related mitochondrial impairment in M\u00fcller cells contributes to the pathogenesis of retinitis pigmentosa in USH3A. These findings identify M\u00fcller cell mitochondrial dysfunction as a key disease mechanism and highlight potential therapeutic targets.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cns.71068","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T14:25:31Z","timestamp":1785767131000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["CLRN1 Variants in M\u00fcller Cells Cause Mitochondrial Dysfunction in USH3A Retinal Organoids"],"prefix":"10.1002","volume":"32","author":[{"given":"Rui","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Ophthalmology Qilu Hospital of Shandong University  Jinan China"},{"name":"Department of Neurology, Research Institute of Neuromuscular and Neurodegenerative Diseases Qilu Hospital of Shandong University, Shandong Key Laboratory of Mitochondrial Medicine and Rare Diseases  Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinbo","family":"Ji","sequence":"additional","affiliation":[{"name":"Department of Neurology, Research Institute of Neuromuscular and Neurodegenerative Diseases Qilu Hospital of Shandong University, Shandong Key Laboratory of Mitochondrial Medicine and Rare Diseases  Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology Qilu Hospital of Shandong University  Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingwen","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Neurology, Research Institute of Neuromuscular and Neurodegenerative Diseases Qilu Hospital of Shandong University, Shandong Key Laboratory of Mitochondrial Medicine and Rare Diseases  Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Wang","sequence":"additional","affiliation":[{"name":"Prenatal Diagnostic Center of Obstetrics and Department of Gynecology Qilu Hospital of Shandong University  Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Sun","sequence":"additional","affiliation":[{"name":"Prenatal Diagnostic Center of Obstetrics and Department of Gynecology Qilu Hospital of Shandong University  Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingxin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Research Institute of Neuromuscular and Neurodegenerative Diseases Qilu Hospital of Shandong University, Shandong Key Laboratory of Mitochondrial Medicine and Rare Diseases  Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-3888-0185","authenticated-orcid":false,"given":"Yao","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Research Institute of Neuromuscular and Neurodegenerative Diseases Qilu Hospital of Shandong University, Shandong Key Laboratory of Mitochondrial Medicine and Rare Diseases  Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zexin","family":"Zhan","sequence":"additional","affiliation":[{"name":"Department of Neurology, Research Institute of Neuromuscular and Neurodegenerative Diseases Qilu Hospital of Shandong University, Shandong Key Laboratory of Mitochondrial Medicine and Rare Diseases  Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-2703-1912","authenticated-orcid":false,"given":"Yichang","family":"Jiao","sequence":"additional","affiliation":[{"name":"Department of Neurology, Research Institute of Neuromuscular and Neurodegenerative Diseases Qilu Hospital of Shandong University, Shandong Key Laboratory of Mitochondrial Medicine and Rare Diseases  Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Didi","family":"Shan","sequence":"additional","affiliation":[{"name":"Department of Neurology, Research Institute of Neuromuscular and Neurodegenerative Diseases Qilu Hospital of Shandong University, Shandong Key Laboratory of Mitochondrial Medicine and Rare Diseases  Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengfei","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Neurology, Research Institute of Neuromuscular and Neurodegenerative Diseases Qilu Hospital of Shandong University, Shandong Key Laboratory of Mitochondrial Medicine and Rare Diseases  Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong\u2010dong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Research Institute of Neuromuscular and Neurodegenerative Diseases Qilu Hospital of Shandong University, Shandong Key Laboratory of Mitochondrial Medicine and Rare Diseases  Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0695-3238","authenticated-orcid":false,"given":"Yuying","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Neurology, Research Institute of Neuromuscular and Neurodegenerative Diseases Qilu Hospital of Shandong University, Shandong Key Laboratory of Mitochondrial Medicine and Rare Diseases  Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianyang","family":"Liu","sequence":"additional","affiliation":[{"name":"Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital Capital Medical University, Beijing Ophthalmology &amp; Visual Sciences Key Laboratory  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2191-5184","authenticated-orcid":false,"given":"Chuanzhu","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Neurology, Research Institute of Neuromuscular and Neurodegenerative Diseases Qilu Hospital of Shandong University, Shandong Key Laboratory of Mitochondrial Medicine and Rare Diseases  Jinan China"},{"name":"Qingdao Municipal Key Laboratory of Mitochondria Medicine  Qingdao China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9288-2703","authenticated-orcid":false,"given":"Jianqiao","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology Qilu Hospital of Shandong University  Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7959-6008","authenticated-orcid":false,"given":"Mingfeng","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Innovation Center for Brain Medical Sciences, Tongji Medical College Huazhong University of Science and Technology, the Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8882-4172","authenticated-orcid":false,"given":"Fuchen","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Neurology, Research Institute of Neuromuscular and Neurodegenerative Diseases Qilu Hospital of Shandong University, Shandong Key Laboratory of Mitochondrial Medicine and Rare Diseases  Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7796-8891","authenticated-orcid":false,"given":"Shengping","family":"Hou","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology Qilu Hospital of Shandong University  Jinan China"},{"name":"Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital Capital Medical University, Beijing Ophthalmology &amp; Visual Sciences Key Laboratory  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,3]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-0004.1997.tb02480.x"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-0004.2004.00352.x"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.40.10.767"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI94351"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201404016"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0311-12.2012"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.003160"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/path.5360"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1000607"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1089\/gtmb.2016.0051"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/mgg3.1131"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13287-020-01883-5"},{"issue":"7","key":"e_1_2_10_14_1","doi-asserted-by":"crossref","first-page":"1970","DOI":"10.1002\/dvdy.21128","article-title":"Nr2e3 and Nrl Can Reprogram Retinal Precursors to the Rod Fate in Xenopus Retina","volume":"236","author":"McIlvain V. A.","year":"2007","journal-title":"Developmental Dynamics: An Official Publication of the American Association of the Anatomists"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.09-4299"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/7678"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1006\/geno.1996.0085"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.heares.2009.06.006"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/stem.2742"},{"key":"e_1_2_10_20_1","volume-title":"Molecular and Functional Characterisation of M\u00fcller Glia Derived From Retinal Organoids Formed by Human Pluripotent Stem Cells (hPSCs)","author":"Wang W.","year":"2020"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20153610"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.11-192914"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.exer.2009.04.012"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/dneu.20798"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1089\/dna.1995.14.313"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-319-75402-4_37"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-8993(99)01552-8"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.62.9.38"},{"issue":"6","key":"e_1_2_10_29_1","article-title":"Mitochondrial Deoxyribonucleic Acid (mtDNA), Maternal Inheritance, and Their Role in the Development of Cancers: A Scoping Review","volume":"15","author":"Vadakedath S.","year":"2023","journal-title":"Cureus"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awr180"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2016.03.021"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/sctm.18-0263"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2012.05.009"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1288\/00005537-198901000-00014"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms5047"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.08.013"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1086\/323610"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11033-024-09565-8"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-01577-8"},{"key":"e_1_2_10_40_1","first-page":"1806","article-title":"Disease\u2010Causing Mutations in the CLRN1 Gene Alter Normal CLRN1 Protein Trafficking to the Plasma Membrane","volume":"15","author":"Isosomppi J.","year":"2009","journal-title":"Molecular Vision"},{"key":"e_1_2_10_41_1","article-title":"Unilateral Retinitis Pigmentosa Occurring in an Individual With a Mutation in the CLRN1 Gene","volume":"2018","author":"Sim P. Y.","year":"2018","journal-title":"Case Reports"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1086\/342098"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1080\/14992020500060610"},{"key":"e_1_2_10_44_1","first-page":"3070","article-title":"Two Novel Disease\u2010Causing Mutations in the CLRN1 Gene in Patients With Usher Syndrome Type 3","volume":"18","author":"Garc\u00eda\u2010Garc\u00eda G.","year":"2012","journal-title":"Molecular Vision"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2010.10.047"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1817500116"},{"key":"e_1_2_10_47_1","first-page":"1197","article-title":"Gene Expression Changes Within M\u00fcller Glial Cells in Retinitis Pigmentosa","volume":"18","author":"Roesch K.","year":"2012","journal-title":"Molecular Vision"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-017-0175-y"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1186\/1742-2094-9-221"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00417-006-0516-y"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2022.1079498"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.preteyeres.2018.11.002"},{"key":"e_1_2_10_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2019.10.008"},{"key":"e_1_2_10_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mito.2017.02.002"},{"key":"e_1_2_10_55_1","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.23583"},{"key":"e_1_2_10_56_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.22477"},{"key":"e_1_2_10_57_1","doi-asserted-by":"publisher","DOI":"10.1097\/WNO.0b013e318272c643"},{"key":"e_1_2_10_58_1","doi-asserted-by":"publisher","DOI":"10.1080\/13816810.2025.2521647"},{"key":"e_1_2_10_59_1","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.66.1.17"},{"key":"e_1_2_10_60_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-024-52391-y"}],"container-title":["CNS Neuroscience &amp; Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cns.71068","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cns.71068","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cns.71068","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T07:01:20Z","timestamp":1787900480000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/cns.71068"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8]]},"references-count":59,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2026,8]]}},"alternative-id":["10.1002\/cns.71068"],"URL":"https:\/\/doi.org\/10.1002\/cns.71068","archive":["Portico"],"relation":{},"ISSN":["1755-5930","1755-5949"],"issn-type":[{"value":"1755-5930","type":"print"},{"value":"1755-5949","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8]]},"assertion":[{"value":"2024-10-08","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-22","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-03","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e71068"}}