Loss-of-Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder.

IF 8.1 1区医学 Q1 CLINICAL NEUROLOGY Annals of Neurology Pub Date : 2024-09-20 DOI:10.1002/ana.27077

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 F Morel, Jordan Lerner-Ellis, Stephanie DiTroia, Magalie Barth, Dominique Bonneau, Ingrid 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 Michael Krawitz, Evan E Eichler, Marco Tartaglia, Sébastien Küry, Tianyun Wang

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Abstract

Objective: 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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CUL3的功能缺失变异导致综合神经发育障碍

目的：cullin-3泛素连接酶（CUL3）的新变异与神经发育障碍（NDDs）密切相关，但迄今为止尚未有大规模的病例报道。在此，我们旨在收集携带CUL3罕见变异的散发性病例，描述基因型与表型的相关性，并研究其潜在的致病机制：方法：通过多中心合作收集遗传数据和详细的临床记录。方法：通过多中心合作收集遗传数据和详细的临床记录，使用 GestaltMatcher 分析畸形面部特征。使用患者衍生 T 细胞评估变异对 CUL3 蛋白稳定性的影响：我们收集了37名具有杂合子CUL3变异的个体，这些个体表现为以智力障碍为特征的综合型NDD，伴有或不伴有自闭症特征。其中，35 例为功能缺失（LoF）变异，2 例为错义变异。患者体内的 CUL3 LoF 变异可能会影响蛋白质的稳定性，导致蛋白质平衡紊乱，体外泛素-蛋白质共轭物的减少就是证明。值得注意的是，我们发现在患者衍生细胞中，CUL3的主要底物4E-BP1（EIF4EBP1）未能成为蛋白酶体降解的靶标：我们的研究进一步完善了CUL3相关神经精神疾病的临床和突变谱，扩展了cullin RING E3连接酶相关神经精神疾病的谱系，并提示通过LoF变体导致的单倍体功能缺失是主要的致病机制。ann neurol 2024.

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来源期刊

Annals of Neurology 医学-临床神经学

CiteScore

18.00

自引率

1.80%

发文量

270

审稿时长

3-8 weeks

期刊介绍： Annals of Neurology publishes original articles with potential for high impact in understanding the pathogenesis, clinical and laboratory features, diagnosis, treatment, outcomes and science underlying diseases of the human nervous system. Articles should ideally be of broad interest to the academic neurological community rather than solely to subspecialists in a particular field. Studies involving experimental model system, including those in cell and organ cultures and animals, of direct translational relevance to the understanding of neurological disease are also encouraged.