{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T01:42:48Z","timestamp":1794015768529,"version":"4.8.0"},"reference-count":54,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2024,9,20]],"date-time":"2024-09-20T00:00:00Z","timestamp":1726790400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2025,1]]},"abstract":"Objective<\/jats:title>De novo variants in cullin\u20103 ubiquitin ligase<\/jats:italic> (CUL3<\/jats:italic>) have been strongly associated with neurodevelopmental disorders (NDDs), but no large case series have been reported so far. Here, we aimed to collect sporadic cases carrying rare variants in CUL3<\/jats:italic>, describe the genotype\u2013phenotype correlation, and investigate the underlying pathogenic mechanism.<\/jats:p><\/jats:sec>Methods<\/jats:title>Genetic data and detailed clinical records were collected via multicenter collaboration. Dysmorphic facial features were analyzed using GestaltMatcher. Variant effects on CUL3 protein stability were assessed using patient\u2010derived T\u2010cells.<\/jats:p><\/jats:sec>Results<\/jats:title>We assembled a cohort of 37 individuals with heterozygous CUL3<\/jats:italic> variants presenting a syndromic NDD characterized by intellectual disability with or without autistic features. Of these, 35 have loss\u2010of\u2010function (LoF) and 2 have missense variants. CUL3<\/jats:italic> LoF variants in patients may affect protein stability leading to perturbations in protein homeostasis, as evidenced by decreased ubiquitin\u2010protein conjugates in vitro. Notably, we show that 4E\u2010BP1 (EIF4EBP1), a prominent substrate of CUL3, fails to be targeted for proteasomal degradation in patient\u2010derived cells.<\/jats:p><\/jats:sec>Interpretation<\/jats:title>Our study further refines the clinical and mutational spectrum of CUL3<\/jats:italic>\u2010associated NDDs, expands the spectrum of cullin RING E3 ligase\u2010associated neuropsychiatric disorders, and suggests haploinsufficiency via LoF variants is the predominant pathogenic mechanism. ANN NEUROL 2025;97:76\u201389<\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.27077","type":"journal-article","created":{"date-parts":[[2024,9,20]],"date-time":"2024-09-20T09:46:15Z","timestamp":1726825575000},"page":"76-89","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Loss\u2010of\u2010Function Variants in CUL3<\/i><\/scp> Cause a Syndromic Neurodevelopmental Disorder"],"prefix":"10.1002","volume":"97","author":[{"given":"Patrick R.","family":"Blackburn","sequence":"first","affiliation":[{"name":"Department of Pathology St. Jude Children's Research Hospital Memphis TN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fr\u00e9d\u00e9ric","family":"Ebstein","sequence":"additional","affiliation":[{"name":"Institute of Medical Biochemistry and Molecular Biology University Medicine Greifswald Greifswald Germany"},{"name":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l'institut du Thorax Nantes France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tzung\u2010Chien","family":"Hsieh","sequence":"additional","affiliation":[{"name":"Institute of Genomic Statistics and Bioinformatics University of Bonn Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marialetizia","family":"Motta","sequence":"additional","affiliation":[{"name":"Molecular Genetics and Functional Genomics Ospedale Pediatrico Bambino Ges\u00f9, IRCCS Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca Clementina","family":"Radio","sequence":"additional","affiliation":[{"name":"Molecular Genetics and Functional Genomics Ospedale Pediatrico Bambino Ges\u00f9, IRCCS Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna C.","family":"Herkert","sequence":"additional","affiliation":[{"name":"Department of Genetics University of Groningen, University Medical Center Groningen Groningen The 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