{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T09:21:40Z","timestamp":1787908900329,"version":"build-2784847793"},"reference-count":41,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T00:00:00Z","timestamp":1787875200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T00:00:00Z","timestamp":1787875200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100021171","name":"Basic and Applied Basic Research Foundation of Guangdong Province","doi-asserted-by":"publisher","award":["2024B1515040019"],"award-info":[{"award-number":["2024B1515040019"]}],"id":[{"id":"10.13039\/501100021171","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100015956","name":"Special Project for Research and Development in Key areas of Guangdong Province","doi-asserted-by":"publisher","award":["2023B0303010001"],"award-info":[{"award-number":["2023B0303010001"]}],"id":[{"id":"10.13039\/501100015956","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31971140"],"award-info":[{"award-number":["31971140"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FEBS Journal"],"abstract":"<jats:p>\n                    Mutations in the\n                    <jats:italic>USH1G<\/jats:italic>\n                    gene, which encodes the scaffold protein SANS, cause type\u2010I Usher syndrome, a severe inherited disorder involving both hearing and vision loss. Although SANS has been implicated in nuclear pre\u2010mRNA splicing, the molecular determinants of its nuclear import and their relevance to USH1G pathogenesis remain incompletely understood. Here, we report high\u2010resolution crystal structures of the N\u2010terminal ankyrin repeat regions of SANS and its homolog ANKS4B. We show that SANS_AR functions as a self\u2010sufficient module that promotes nuclear localization, whereas ANKS4B_AR lacks this property. Structure\u2010guided analysis of USH1G\u2010associated variants suggests two distinct classes of effects: core hydrophobic mutations such as L48P, L84P impair SANS_AR solubility and are predicted to destabilize the domain, whereas surface\u2010exposed substitutions such as R10W, S119P, and R146C remain compatible with soluble expression but reduce SANS nuclear localization. Together, these findings provide a molecular framework for understanding how impaired SANS_AR stability and defective nuclear localization may contribute to USH1G pathogenesis.\n                  <\/jats:p>","DOI":"10.1111\/febs.70708","type":"journal-article","created":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T09:06:51Z","timestamp":1787908011000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>SANS<\/scp>\n                    ankyrin repeats mediate non\u2010classical nuclear import and dictate distinct pathogenic mechanisms"],"prefix":"10.1111","author":[{"given":"Wenxia","family":"Yan","sequence":"first","affiliation":[{"name":"Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital  Taiyuan China"},{"name":"Innovation Centre of Ministry of Education for Development and Diseases, School of Medicine South China University of Technology  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guanhao","family":"Chen","sequence":"additional","affiliation":[{"name":"Innovation Centre of Ministry of Education for Development and Diseases, School of Medicine South China University of Technology  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liping","family":"Wang","sequence":"additional","affiliation":[{"name":"Innovation Centre of Ministry of Education for Development and Diseases, School of Medicine South China University of Technology  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8921-1626","authenticated-orcid":false,"given":"Jianchao","family":"Li","sequence":"additional","affiliation":[{"name":"Innovation Centre of Ministry of Education for Development and Diseases, School of Medicine South China University of Technology  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,28]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1038\/s41576-023-00597-7","article-title":"Deafness: from genetic architecture to gene therapy","volume":"24","author":"Petit C","year":"2023","journal-title":"Nat Rev Genet"},{"key":"e_1_2_10_3_1","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1007\/s00439-022-02448-7","article-title":"The genetic and phenotypic landscapes of usher syndrome: from disease mechanisms to a new classification","volume":"141","author":"Delmaghani S","year":"2022","journal-title":"Hum Genet"},{"key":"e_1_2_10_4_1","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1016\/j.bbadis.2014.11.020","article-title":"Usher syndrome: hearing loss, retinal degeneration and associated abnormalities","volume":"1852","author":"Mathur P","year":"2015","journal-title":"Biochim Biophys 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L","year":"2011","journal-title":"Science"},{"key":"e_1_2_10_8_1","doi-asserted-by":"crossref","first-page":"4040","DOI":"10.1073\/pnas.0911385107","article-title":"The structure of the harmonin\/sans complex reveals an unexpected interaction mode of the two usher syndrome proteins","volume":"107","author":"Yan J","year":"2010","journal-title":"Proc Natl Acad Sci U S A"},{"key":"e_1_2_10_9_1","doi-asserted-by":"crossref","first-page":"974","DOI":"10.1016\/j.celrep.2019.09.027","article-title":"Myosin VII, USH1C, and ANKS4B or USH1G together form condensed molecular assembly via liquid\u2010liquid phase separation","volume":"29","author":"He Y","year":"2019","journal-title":"Cell Rep"},{"key":"e_1_2_10_10_1","doi-asserted-by":"crossref","first-page":"1883","DOI":"10.1016\/j.bbamcr.2011.05.015","article-title":"Direct interaction of the usher syndrome 1G protein SANS and myomegalin in the retina","volume":"1813","author":"Overlack N","year":"2011","journal-title":"Biochim Biophys 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Res"},{"key":"e_1_2_10_14_1","doi-asserted-by":"crossref","DOI":"10.3390\/cells13221855","article-title":"Nuclear\u2010cytoplasmic shuttling of the usher syndrome 1G protein SANS differs from its paralog ANKS4B","volume":"13","author":"Fritze JS","year":"2024","journal-title":"Cells"},{"key":"e_1_2_10_15_1","doi-asserted-by":"crossref","first-page":"5101","DOI":"10.1074\/jbc.R600026200","article-title":"Classical nuclear localization signals: definition, function, and interaction with importin alpha","volume":"282","author":"Lange A","year":"2007","journal-title":"J Biol Chem"},{"key":"e_1_2_10_16_1","doi-asserted-by":"crossref","first-page":"16029","DOI":"10.1073\/pnas.252537899","article-title":"Consensus\u2010derived structural determinants of the ankyrin repeat motif","volume":"99","author":"Mosavi LK","year":"2002","journal-title":"Proc Natl Acad Sci U S A"},{"key":"e_1_2_10_17_1","doi-asserted-by":"crossref","first-page":"1435","DOI":"10.1110\/ps.03554604","article-title":"The ankyrin repeat as molecular architecture for protein recognition","volume":"13","author":"Mosavi LK","year":"2004","journal-title":"Protein Sci"},{"key":"e_1_2_10_18_1","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/S0968-0004(99)01426-7","article-title":"The ankyrin repeat: a diversity of interactions on a common structural framework","volume":"24","author":"Sedgwick SG","year":"1999","journal-title":"Trends Biochem Sci"},{"key":"e_1_2_10_19_1","doi-asserted-by":"crossref","first-page":"5750","DOI":"10.1111\/febs.70178","article-title":"Deciphering the family of ankyrin repeat\u2010containing proteins of plasmodium falciparum: a structural and functional perspective","volume":"292","author":"Kumari P","year":"2025","journal-title":"FEBS J"},{"key":"e_1_2_10_20_1","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1093\/hmg\/ddg051","article-title":"Usher syndrome type I G (USH1G) is caused by mutations in the gene encoding SANS, a protein that associates with the USH1C protein, harmonin","volume":"12","author":"Weil D","year":"2003","journal-title":"Hum Mol Genet"},{"key":"e_1_2_10_21_1","doi-asserted-by":"crossref","first-page":"1130","DOI":"10.1016\/j.cell.2014.05.006","article-title":"A code for RanGDP binding in ankyrin repeats defines a nuclear import pathway","volume":"157","author":"Lu M","year":"2014","journal-title":"Cell"},{"key":"e_1_2_10_22_1","doi-asserted-by":"crossref","first-page":"2524","DOI":"10.1128\/MCB.18.5.2524","article-title":"Nuclear localization of IkappaB alpha is mediated by the second ankyrin repeat: the IkappaB alpha ankyrin repeats define a novel class of cis\u2010acting nuclear import sequences","volume":"18","author":"Sachdev S","year":"1998","journal-title":"Mol Cell Biol"},{"key":"e_1_2_10_23_1","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1111\/j.1365-2443.2004.00776.x","article-title":"Harp (harmonin\u2010interacting, ankyrin repeat\u2010containing protein), a novel protein that interacts with harmonin in epithelial tissues","volume":"9","author":"Johnston AM","year":"2004","journal-title":"Genes Cells"},{"key":"e_1_2_10_24_1","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.devcel.2015.12.022","article-title":"ANKS4B is essential for Intermicrovillar adhesion complex formation","volume":"36","author":"Crawley SW","year":"2016","journal-title":"Dev Cell"},{"key":"e_1_2_10_25_1","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.devcel.2015.12.020","article-title":"Mechanistic basis of Organization of the Harmonin\/USH1C\u2010mediated brush border microvilli tip\u2010link complex","volume":"36","author":"Li J","year":"2016","journal-title":"Dev Cell"},{"key":"e_1_2_10_26_1","first-page":"E3776","article-title":"Structure of Myo7b\/USH1C complex suggests a general PDZ domain binding mode by MyTH4\u2010FERM myosins","volume":"114","author":"Li J","year":"2017","journal-title":"Proc Natl Acad Sci U S 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recognitions by ankyrins","volume":"3","author":"Wang C","year":"2014","journal-title":"Elife"},{"key":"e_1_2_10_31_1","doi-asserted-by":"crossref","first-page":"902","DOI":"10.1016\/j.celrep.2012.09.004","article-title":"Innate immune messenger 2\u20105A tethers human RNase L into active high\u2010order complexes","volume":"2","author":"Han Y","year":"2012","journal-title":"Cell Rep"},{"key":"e_1_2_10_32_1","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.12856","article-title":"Myosin III\u2010mediated cross\u2010linking and stimulation of actin bundling activity of Espin","volume":"5","author":"Liu H","year":"2016","journal-title":"Elife"},{"key":"e_1_2_10_33_1","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pcbi.1008543","article-title":"PremPS: predicting the impact of missense mutations on protein stability","volume":"16","author":"Chen Y","year":"2020","journal-title":"PLoS Comput 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Tracing protein chains","volume":"62","author":"Cowtan K","year":"2006","journal-title":"Acta Crystallogr D Biol Crystallogr"},{"key":"e_1_2_10_41_1","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1107\/S0907444910007493","article-title":"Features and development of Coot","volume":"66","author":"Emsley P","year":"2010","journal-title":"Acta Crystallogr D Biol Crystallogr"},{"key":"e_1_2_10_42_1","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1107\/S0907444909052925","article-title":"PHENIX: a comprehensive python\u2010based system for macromolecular structure solution","volume":"66","author":"Adams PD","year":"2010","journal-title":"Acta Crystallogr D Biol Crystallogr"}],"container-title":["The FEBS Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/febs.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/febs.70708","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/febs.onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/febs.70708","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/febs.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/febs.70708","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T09:06:56Z","timestamp":1787908016000},"score":1,"resource":{"primary":{"URL":"https:\/\/febs.onlinelibrary.wiley.com\/doi\/10.1111\/febs.70708"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,28]]},"references-count":41,"alternative-id":["10.1111\/febs.70708"],"URL":"https:\/\/doi.org\/10.1111\/febs.70708","archive":["Portico"],"relation":{},"ISSN":["1742-464X","1742-4658"],"issn-type":[{"value":"1742-464X","type":"print"},{"value":"1742-4658","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,28]]},"assertion":[{"value":"2026-04-28","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-11","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-28","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"febs.70708"}}