Loss‐of‐Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder
2024; Wiley; Linguagem: Inglês
10.1002/ana.27077
ISSN1531-8249
AutoresPatrick R. Blackburn, Frédéric Ebstein, Tzung‐Chien Hsieh, Marialetizia Motta, Francesca Clementina Radio, Johanna C. Herkert, Tuula Rinne, Isabelle Thiffault, Michele Rapp, Mariel Alders, Saskia M. Maas, Bénédicte Gérard, Thomas Smol, Catherine Vincent‐Delorme, Benjamin Cogné, Bertrand Isidor, Marie Vincent, Ruxandra Bachmann‐Gagescu, Anita Rauch, Pascal Joset, Giovanni Battista Ferrero, Andrea Ciolfi, Thomas Husson, Anne‐Marie Guerrot, Carlos A. Bacino, Colleen Macmurdo, Stephanie S. Thompson, Jill A. Rosenfeld, Laurence Faivre, Frédéric Tran Mau‐Them, Wallid Deb, Virginie Vignard, Pankaj B. Agrawal, Jill A. Madden, Alice Goldenberg, François Lecoquierre, Michael Zech, Holger Prokisch, Ján Necpál, Robert Jech, Juliane Winkelmann, Monika Turčanová Koprušáková, Vassiliki Konstantopoulou, John R. Younce, Marwan Shinawi, Chloe Mighton, Charlotte Fung, Chantal F. Morel, Jordan Lerner‐Ellis, Stephanie DiTroia, Magalie Barth, Dominique Bonneau, Ingrid P.C. Krapels, Alexander P.A. Stegmann, Vyne van der Schoot, Theresa Brunet, Cornelia Bußmann, Cyril Mignot, Giuseppe Zampino, Saskia B. Wortmann, Johannes A. Mayr, René G. Feichtinger, Thomas Courtin, Claudia Ravelli, Boris Keren, Alban Ziegler, Linda Hasadsri, Pavel N. Pichurin, Eric W. Klee, Katheryn Grand, Pedro A. Sanchez‐Lara, Elke Krüger, Stéphane Bézieau, Hannah Klinkhammer, Peter Krawitz, Evan E. Eichler, Marco Tartaglia, Sébastien Küry, Tianyun Wang,
Tópico(s)Genomics and Rare Diseases
ResumoObjective De 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. Methods 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‐derived T‐cells. Results We 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. Interpretation Our 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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