ArticleAnnals of neurology2024
Loss-of-Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder.
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Article in Annals of neurology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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15 citing papers in PubMed.
- A Selective Cullin 3 RING E3 Ligase Inhibitor Attenuates Hyperglycemia via Dual Insulin Sensitizing and Insulinotropic Action.Diabetes · 2026Article
- Review
- Impaired Activity-Regulated Proteostasis: A Shared Mechanism in Neurodevelopmental Disorders.Biological psychiatry · 2026Review
- Collaborative Genomics for Dystonia in Central and Eastern Europe: Successes Achieved, New Frontiers Ahead.Movement disorders : official journal of the Movement Disorder Society · 2026Article
- CUL3-Related Neurodevelopmental Disorder: Expanding the Prenatal Phenotype.Prenatal diagnosis · 2026Article
- Recessive variants in WSB2 encoding a substrate receptor of E3 ubiquitin ligase underlie a neurodevelopmental syndrome.European journal of human genetics : EJHG · 2026Article
- Adipose cullin 3 mediates the antiobesity effect of pan neddylation inhibitors.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Clinical Application of a Customized Gene Panel for Identifying Autism Spectrum Disorder-Associated Variants.Medicina (Kaunas, Lithuania) · 2025Article
- Article
- Artificial intelligence-driven genotype-epigenotype-phenotype approaches to resolve challenges in syndrome diagnostics.EBioMedicine · 2025Article
- Discovery of a NovelMolecular syndromology · 2025Article
- GestaltMatcher Database - A global reference for facial phenotypic variability in rare human diseases.medRxiv : the preprint server for health sciences · 2024Article
- GestaltMatcher Database - A global reference for facial phenotypic variability in rare human diseases.Research square · 2024Article
- Cullin 3 RING E3 ligase inactivation causes NRF2-dependent NADH reductive stress, hepatic lipodystrophy, and systemic insulin resistance.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Cullin-3 proteins be a novel biomarkers and therapeutic targets for hyperchloremia induced by oral poisoning.Scientific reports · 2024Article
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Authors and funding
79 authors.
Patrick R BlackburnDepartment of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.
Frédéric EbsteinInstitute of Medical Biochemistry and Molecular Biology, University Medicine Greifswald, Greifswald, Germany.
Tzung-Chien HsiehInstitute of Genomic Statistics and Bioinformatics, University of Bonn, Bonn, Germany.
Marialetizia MottaMolecular Genetics and Functional Genomics, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
Francesca Clementina RadioMolecular Genetics and Functional Genomics, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
Johanna C HerkertDepartment of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Tuula RinneDepartment of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
Isabelle ThiffaultCenter for Pediatric Genomic Medicine, Children's Mercy Hospital, Kansas City, MO, USA.
Michele RappDepartment of Pediatrics-Clinical Genetics and Metabolism, Children's Hospital Colorado, Aurora, CO, USA.
Mariel AldersAmsterdam University Medical Center, University of Amsterdam, Department of Clinical Genetics, Amsterdam, The Netherlands.
Saskia MaasAmsterdam University Medical Center, University of Amsterdam, Department of Clinical Genetics, Amsterdam, The Netherlands.
Bénédicte GerardUnité de Biologie et de Génétique Moléculaire, Center Hospitalier Universitaire de Strasbourg, Strasbourg, France.
Thomas SmolUniv Lille, CHU Lille, RADEME Team, Institut de Génétique Médicale, Lille, France.
Catherine Vincent-DelormeDepartment of Clinical Genetics, Hôpital Jeanne de Flandre, CHU Lille, Lille, France.
Benjamin CognéNantes Université, CHU Nantes, CNRS, INSERM, l'institut du Thorax, Nantes, France.
Bertrand IsidorNantes Université, CHU Nantes, CNRS, INSERM, l'institut du Thorax, Nantes, France.
Marie VincentNantes Université, CHU Nantes, CNRS, INSERM, l'institut du Thorax, Nantes, France.
Ruxandra Bachmann-GagescuInstitute of Medical Genetics, University of Zurich, Schlieren, Switzerland.
Anita RauchInstitute of Medical Genetics, University of Zurich, Schlieren, Switzerland.
Pascal JosetMedical Genetics, Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland.
Giovanni Battista FerreroDepartment of Clinical and Biological Sciences, San Luigi Gonzaga University Hospital, University of Torino, Turin, Italy.
Andrea CiolfiMolecular Genetics and Functional Genomics, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
Thomas HussonDepartment of Research, Center Hospitalier du Rouvray, Rouen, France.
Anne-Marie GuerrotNormandie Univ, UNIROUEN, Inserm U1245 and CHU Rouen, Department of Genetics and Reference Center for Developmental Disorders, Rouen, France.
Carlos BacinoDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Colleen MacmurdoDivision of Medical Genetics, Department of Internal Medicine, Baylor Scott and White Medical Center, Temple, TX, USA.
Stephanie S ThompsonDivision of Medical Genetics, Department of Internal Medicine, Baylor Scott and White Medical Center, Temple, TX, USA.
Jill A RosenfeldDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Laurence FaivreCentre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs, FHU TRANSLAD CHU, Dijon, France.
Frederic Tran Mau-ThemINSERM UMR1231, équipe GAD, Université de Bourgogne-Franche Comté, Dijon, France.
Wallid DebNantes Université, CHU Nantes, CNRS, INSERM, l'institut du Thorax, Nantes, France.
Virginie VignardNantes Université, CHU Nantes, CNRS, INSERM, l'institut du Thorax, Nantes, France.
Pankaj B AgrawalDivision of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston, MA, USA.
Jill A MaddenDivision of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston, MA, USA.
Alice GoldenbergNormandie Univ, UNIROUEN, Inserm U1245 and CHU Rouen, Department of Genetics and Reference Center for Developmental Disorders, Rouen, France.
François LecoquierreNormandie Univ, UNIROUEN, Inserm U1245 and CHU Rouen, Department of Genetics and Reference Center for Developmental Disorders, Rouen, France.
Michael ZechInstitute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany.
Holger ProkischInstitute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany.ORCID https://orcid.org/0000-0003-2379-6286
Ján NecpálDepartment of Neurology, Zvolen Hospital, Zvolen, Slovakia.
Robert JechDepartment of Neurology, Charles University, First Faculty of Medicine and General University Hospital, Prague, Czech Republic.
Juliane WinkelmannInstitute of Neurogenomics, Helmholtz Zentrum Muenchen, Neuherberg, Germany.
Monika Turčanová KoprušákováJessenius Faculty of Medicine in Martin, Comenius University Bratislava, Martin, Slovakia.
Vassiliki KonstantopoulouDepartment of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
John R YounceDepartment of Neurology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Marwan ShinawiDivision of Genetics and Genomic Medicine, St. Louis Children's Hospital, St. Louis, MO, USA.ORCID https://orcid.org/0000-0003-1329-4100
Chloe MightonInstitute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada.
Charlotte FungThe Fred A. Litwin Family Centre in Genetic Medicine, University Health Network and Sinai Health System, Toronto, Canada.
Chantal F MorelThe Fred A. Litwin Family Centre in Genetic Medicine, University Health Network and Sinai Health System, Toronto, Canada.
Jordan Lerner-EllisPathology and Laboratory Medicine, Mount Sinai Hospital, Sinai Health, Toronto, Canada.
Stephanie DiTroiaCenter for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Magalie BarthDepartment of Biochemistry and Genetics, University Hospital of Angers, Angers, France.
Dominique BonneauDepartment of Biochemistry and Genetics, University Hospital of Angers, Angers, France.
Ingrid KrapelsDepartment of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.
Alexander P A StegmannDepartment of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.
Vyne van der SchootDepartment of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.
Theresa BrunetInstitute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany.ORCID https://orcid.org/0000-0002-5183-780X
Cornelia BußmannDepartment of Neuropediatrics, ATOS Klinik Heidelberg, Heidelberg, Germany.
Cyril MignotDépartement de Génétique, AP-HP-Sorbonne Université, Hôpital Trousseau & Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
Giuseppe ZampinoCenter for Rare Diseases and Birth Defects, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.
Saskia B WortmannUniversity Children's Hospital, Paracelsus Medical University (PMU), Salzburg, Austria.
Johannes A MayrUniversity Children's Hospital, Paracelsus Medical University (PMU), Salzburg, Austria.
René G FeichtingerUniversity Children's Hospital, Paracelsus Medical University (PMU), Salzburg, Austria.
Thomas CourtinCenter for Molecular and Chromosomal Genetics, AP-HP-Sorbonne University, Pitié-Salpêtrière Hospital, Paris, France.
Claudia RavelliDepartment of Pediatric Neurology and Neurogenetic Referral Center, AP-HP-Sorbonne Université, Armand Trousseau Hospital, Paris, France.
Boris KerenDépartement de Génétique, AP-HP-Sorbonne Université, Hôpital Trousseau & Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
Alban ZieglerMitovasc Unit, UMR CNRS 6015-INSERM 1083, Angers, France.
Linda HasadsriDivision of Laboratory Genetics and Genomics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
Pavel N PichurinDepartment of Clinical Genomics, Mayo Clinic, Rochester, MN, USA.
Eric W KleeDepartment of Clinical Genomics, Mayo Clinic, Rochester, MN, USA.
Katheryn GrandDepartment of Pediatrics, Guerin Children's at Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Pedro A Sanchez-LaraDepartment of Pediatrics, Guerin Children's at Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Elke KrügerInstitute of Medical Biochemistry and Molecular Biology, University Medicine Greifswald, Greifswald, Germany.
Stéphane BézieauNantes Université, CHU Nantes, CNRS, INSERM, l'institut du Thorax, Nantes, France.
Hannah KlinkhammerInstitute of Genomic Statistics and Bioinformatics, University of Bonn, Bonn, Germany.
Peter Michael KrawitzInstitute of Genomic Statistics and Bioinformatics, University of Bonn, Bonn, Germany.
Evan E EichlerDepartment of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA.
Marco TartagliaMolecular Genetics and Functional Genomics, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.ORCID https://orcid.org/0000-0001-7736-9672
Sébastien KüryNantes Université, CHU Nantes, CNRS, INSERM, l'institut du Thorax, Nantes, France.
Tianyun WangDepartment of Medical Genetics, Center for Medical Genetics, School of Basic Medical Sciences, Peking University, Beijing, China.ORCID https://orcid.org/0000-0002-5179-087X
Funding
Sporadic Mutations and Autism Spectrum DisordersR01MH101221 · NIMH · UNIVERSITY OF WASHINGTON · PI EICHLER, EVAN · 2013 to 2025
$9.2MNIMH NIH HHS R01 MH101221
Abstract
objectiveDe novo variants in cullin-3 ubiquitin ligase (CUL3) 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, describe the genotype-phenotype correlation, and investigate the underlying pathogenic mechanism.
methodsGenetic 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-derived T-cells.
resultsWe assembled a cohort of 37 individuals with heterozygous CUL3 variants presenting a syndromic NDD characterized by intellectual disability with or without autistic features. Of these, 35 have loss-of-function (LoF) and 2 have missense variants. CUL3 LoF variants in patients may affect protein stability leading to perturbations in protein homeostasis, as evidenced by decreased ubiquitin-protein conjugates in vitro. Notably, we show that 4E-BP1 (EIF4EBP1), a prominent substrate of CUL3, fails to be targeted for proteasomal degradation in patient-derived cells.
interpretationOur study further refines the clinical and mutational spectrum of CUL3-associated NDDs, expands the spectrum of cullin RING E3 ligase-associated neuropsychiatric disorders, and suggests haploinsufficiency via LoF variants is the predominant pathogenic mechanism. ANN NEUROL 2024.
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