{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:59:52Z","timestamp":1785427192673,"version":"3.56.0"},"reference-count":19,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T00:00:00Z","timestamp":1779062400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003356","name":"Gazi University","doi-asserted-by":"crossref","award":["TGA-2024-9178"],"award-info":[{"award-number":["TGA-2024-9178"]}],"id":[{"id":"10.13039\/501100003356","id-type":"DOI","asserted-by":"crossref"}]},{"award":["TGA-2024-9178"],"award-info":[{"award-number":["TGA-2024-9178"]}],"id":[{"id":"https:\/\/ror.org\/054xkpr46","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Ring finger protein 43 (RNF43) encodes a transmembrane E3 ubiquitin ligase that negatively regulates canonical Wnt signaling and is classically associated with serrated polyposis syndrome and colorectal cancer. In this study, regarding a homozygous truncating RNF43 variant (NM_001305545.1:c.1906C&gt;T; p.Gln636Ter) in a patient segregating with a severe neurodevelopmental phenotype characterized by developmental delay, neonatal hypotonia, recurrent seizures, progressive microcephaly, and bilateral optic atrophy, the loss of polarity defective 1 (plr-1), an ortholog of RNF43, was modeled in Caenorhabditis elegans and the phenotype was primarily characterized. The results demonstrated that loss of the plr-1 disrupted gamma aminobutyric acid (GABA)ergic axon organization, reduced locomotor speed calculated from 60 s recordings, and altered developmental growth. These findings expand the phenotypic spectrum of RNF43 and support a dosage-dependent developmental role.<\/jats:p>","DOI":"10.3390\/ijms27104509","type":"journal-article","created":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T07:35:43Z","timestamp":1779176143000},"page":"4509","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Functional Characterization of Loss of RNF43 Reveals Neuronal Defects in a Caenorhabditis elegans Model"],"prefix":"10.3390","volume":"27","author":[{"given":"Kaan","family":"Sonmez","sequence":"first","affiliation":[{"name":"Department of Pediatric Surgery, Faculty of Medicine, Gazi University, 06560 Ankara, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-8357-9516","authenticated-orcid":false,"given":"Sinem","family":"G\u00fczel","sequence":"additional","affiliation":[{"name":"Rare Disease Laboratory, School of Life and Natural Sciences, Abdullah Gul University, 38040 Kayseri, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hasan Huseyin","family":"Kazan","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, G\u00fclhane Faculty of Medicine, University of Health Sciences, 06010 Ankara, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Burcu","family":"Ekim","sequence":"additional","affiliation":[{"name":"Laboratory Animals Raising and Experimental Research Center (GUDAM), Gazi University, 06560 Ankara, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4265-4013","authenticated-orcid":false,"given":"Cem","family":"Kaya","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Faculty of Medicine, Gazi University, 06560 Ankara, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zafer","family":"Turkyilmaz","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Faculty of Medicine, Gazi University, 06560 Ankara, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9624-3258","authenticated-orcid":false,"given":"Ramazan","family":"Karabulut","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Faculty of Medicine, Gazi University, 06560 Ankara, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9696-0433","authenticated-orcid":false,"given":"Mehmet Ali","family":"Ergun","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Faculty of Medicine, Gazi University, 06560 Ankara, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1038\/nature11308","article-title":"Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors","volume":"488","author":"Koo","year":"2012","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1038\/nature11019","article-title":"ZNRF3 promotes Wnt receptor turnover in an R-spondin-sensitive manner","volume":"485","author":"Hao","year":"2012","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1101\/gad.235473.113","article-title":"The R-spondin\/Lgr5\/Rnf43 module: Regulator of Wnt signal strength","volume":"28","author":"Peng","year":"2014","journal-title":"Genes Dev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1192","DOI":"10.1016\/j.cell.2012.05.012","article-title":"Wnt\/\u03b2-catenin signaling and disease","volume":"149","author":"Clevers","year":"2012","journal-title":"Cell"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1016\/j.cell.2017.05.016","article-title":"Wnt\/\u03b2-catenin signaling, disease, and emerging therapeutic modalities","volume":"169","author":"Nusse","year":"2017","journal-title":"Cell"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"54788","DOI":"10.18632\/oncotarget.18510","article-title":"MicroRNA16 regulates glioma cell proliferation, apoptosis and invasion by targeting Wip1-ATM-p53 feedback loop","volume":"8","author":"Zhan","year":"2017","journal-title":"Oncotarget"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1264","DOI":"10.1038\/ng.3127","article-title":"RNF43 is frequently mutated in colorectal and endometrial cancers","volume":"46","author":"Giannakis","year":"2014","journal-title":"Nat. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1053\/j.gastro.2013.10.045","article-title":"Germline mutations in oncogene-induced senescence pathways are associated with multiple sessile serrated adenomas","volume":"146","author":"Gala","year":"2014","journal-title":"Gastroenterology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1038\/nrn1665","article-title":"WNTs in the vertebrate nervous system: From patterning to neuronal connectivity","volume":"6","author":"Ciani","year":"2005","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1038\/nature12517","article-title":"Cerebral organoids model human brain development and microcephaly","volume":"501","author":"Lancaster","year":"2013","journal-title":"Nature"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Maro, G.S., Klassen, M.P., and Shen, K. (2009). A \u03b2-catenin-dependent Wnt pathway mediates anteroposterior axon guidance in C. elegans motor neurons. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0004690"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/j.devcel.2006.01.013","article-title":"Wnt signals and frizzled activity orient anterior-posterior axon outgrowth in C. elegans","volume":"10","author":"Hilliard","year":"2006","journal-title":"Dev. Cell"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"D980","DOI":"10.1093\/nar\/gkt1113","article-title":"ClinVar: Public archive of relationships among sequence variation and human phenotype","volume":"42","author":"Landrum","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1016\/j.ibneur.2025.04.004","article-title":"RNF13 variants L311S and L312P associated with developmental epileptic encephalopathy alter dendritic organization in hippocampal neurons","volume":"18","author":"Cabana","year":"2025","journal-title":"IBRO Neurosci. Rep."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Zhang, Q., Yang, Q., Zhou, X., Zhang, S., Ruan, Y., and Luo, J. (2026). A novel de novo RNF13 variant in developmental and epileptic encephalopathy 73: Genotype\u2013phenotype correlation and literature review. BMC Neurol., 26.","DOI":"10.1186\/s12883-026-04651-9"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/j.ajhg.2020.02.011","article-title":"De novo truncating variants in the last exon of SEMA6B cause progressive myoclonic epilepsy","volume":"106","author":"Hamanaka","year":"2020","journal-title":"Am. J. Hum. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"a008003","DOI":"10.1101\/cshperspect.a008003","article-title":"Wnt signaling in the vertebrate central nervous system: From axon guidance to synaptic function","volume":"4","author":"Salinas","year":"2012","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.ydbio.2014.11.008","article-title":"PLR-1, a putative E3 ubiquitin ligase, controls cell polarity and axonal extensions in C. elegans","volume":"398","author":"Bhat","year":"2015","journal-title":"Dev. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1093\/genetics\/77.1.71","article-title":"The genetics of Caenorhabditis elegans","volume":"77","author":"Brenner","year":"1974","journal-title":"Genetics"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/10\/4509\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T04:32:11Z","timestamp":1779251531000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/10\/4509"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,18]]},"references-count":19,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["ijms27104509"],"URL":"https:\/\/doi.org\/10.3390\/ijms27104509","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,18]]}}}