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[Preprint]. 2023 Jun 16:2023.06.13.23290941.
doi: 10.1101/2023.06.13.23290941.

Loss-of-function variants in CUL3 cause a syndromic neurodevelopmental disorder

Patrick R Blackburn, Frédéric Ebstein, Tzung-Chien Hsieh, Marialetizia Motta, Francesca Clementina Radio, Johanna C Herkert, Tuula Rinne, Isabelle Thiffault, Michele Rapp, Mariel Alders, Saskia Maas, Bénédicte Gerard, 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 Bacino, Colleen Macmurdo, Stephanie S Thompson, Jill A Rosenfeld, Laurence Faivre, Frederic 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 Morel, Jordan Lerner- Ellis, Stephanie DiTroia, Magalie Barth, Dominique Bonneau, Ingrid Krapels, Sander Stegmann, Vyne van der Schoot, Theresa Brunet, Cornelia Bußmann, Cyril Mignot, 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 Michael Krawitz, Evan E Eichler, Marco Tartaglia, Sébastien Küry, Tianyun Wang

Loss-of-function variants in CUL3 cause a syndromic neurodevelopmental disorder

Patrick R Blackburn et al. medRxiv. .

Update in

  • Loss-of-Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder.
    Blackburn PR, Ebstein F, Hsieh TC, Motta M, Radio FC, Herkert JC, Rinne T, Thiffault I, Rapp M, Alders M, Maas S, Gerard B, Smol T, Vincent-Delorme C, Cogné B, Isidor B, Vincent M, Bachmann-Gagescu R, Rauch A, Joset P, Ferrero GB, Ciolfi A, Husson T, Guerrot AM, Bacino C, Macmurdo C, Thompson SS, Rosenfeld JA, Faivre L, Mau-Them FT, Deb W, Vignard V, Agrawal PB, Madden JA, Goldenberg A, Lecoquierre F, Zech M, Prokisch H, Necpál J, Jech R, Winkelmann J, Koprušáková MT, Konstantopoulou V, Younce JR, Shinawi M, Mighton C, Fung C, Morel CF, Lerner-Ellis J, DiTroia S, Barth M, Bonneau D, Krapels I, Stegmann APA, van der Schoot V, Brunet T, Bußmann C, Mignot C, Zampino G, Wortmann SB, Mayr JA, Feichtinger RG, Courtin T, Ravelli C, Keren B, Ziegler A, Hasadsri L, Pichurin PN, Klee EW, Grand K, Sanchez-Lara PA, Krüger E, Bézieau S, Klinkhammer H, Krawitz PM, Eichler EE, Tartaglia M, Küry S, Wang T. Blackburn PR, et al. Ann Neurol. 2024 Sep 20:10.1002/ana.27077. doi: 10.1002/ana.27077. Online ahead of print. Ann Neurol. 2024. PMID: 39301775

Abstract

Purpose: De novo variants in CUL3 (Cullin-3 ubiquitin ligase) 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 multi-center 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 35 individuals with heterozygous CUL3 variants presenting a syndromic NDD characterized by intellectual disability with or without autistic features. Of these, 33 have loss-of-function (LoF) and two 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 . Specifically, we show that cyclin E1 (CCNE1) and 4E-BP1 (EIF4EBP1), two prominent substrates of CUL3, fail to be targeted for proteasomal degradation in patient-derived cells.

Conclusion: 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.

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