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

IF 7.7 1区医学 Q1 CLINICAL NEUROLOGY Annals of Neurology Pub Date : 2024-09-20 DOI:10.1002/ana.27077

Patrick R. Blackburn PhD, FACMG, Frédéric Ebstein PhD, Tzung-Chien Hsieh PhD, Marialetizia Motta PhD, Francesca Clementina Radio MD, PhD, Johanna C. Herkert MD, PhD, Tuula Rinne PhD, Isabelle Thiffault PhD, Michele Rapp MS, Mariel Alders MD, PhD, Saskia Maas MD, Bénédicte Gerard PharmD, PhD, Thomas Smol MD, Catherine Vincent-Delorme MD, Benjamin Cogné MD, Bertrand Isidor MD, Marie Vincent MD, Ruxandra Bachmann-Gagescu MD, Anita Rauch MD, Pascal Joset PhD, Giovanni Battista Ferrero MD, PhD, Andrea Ciolfi PhD, Thomas Husson MD, PhD, Anne-Marie Guerrot MD, Carlos Bacino MD, FACMG, Colleen Macmurdo DO, Stephanie S. Thompson MS, CGC, Jill A. Rosenfeld MS, CGC, Laurence Faivre MD, PhD, Frederic Tran Mau-Them MD, PhD, Wallid Deb BSc, Virginie Vignard MS, Pankaj B. Agrawal MD, MMSc, Jill A. Madden PhD, MSc, CGC, Alice Goldenberg MD, François Lecoquierre MD, Michael Zech MD, Holger Prokisch PhD, Ján Necpál MD, Robert Jech MD, PhD, Juliane Winkelmann MD, Monika Turčanová Koprušáková MD, PhD, Vassiliki Konstantopoulou MD, John R. Younce MD, Marwan Shinawi MD, FACMG, Chloe Mighton MSc, Charlotte Fung MSc, CGC, Chantal F. Morel BSc, MD, FRCPC, Jordan Lerner-Ellis PhD, FACMG, Stephanie DiTroia PhD, Magalie Barth MD, Dominique Bonneau MD, PhD, Ingrid Krapels MD, PhD, Alexander P.A. Stegmann PhD, Vyne van der Schoot MD, PhD, Theresa Brunet MD, Cornelia Bußmann MD, Cyril Mignot MD, PhD, Giuseppe Zampino MD, Saskia B. Wortmann MD, PhD, Johannes A. Mayr MD, René G. Feichtinger PhD, Thomas Courtin MD, Claudia Ravelli MD, Boris Keren MD, PhD, Alban Ziegler MD, Linda Hasadsri MD, PhD, Pavel N. Pichurin MD, Eric W. Klee PhD, Katheryn Grand MS, CGC, Pedro A. Sanchez-Lara MD, MSCE, FAAP, FACMG, Elke Krüger PhD, Stéphane Bézieau PharmD, PhD, Hannah Klinkhammer MSc, Peter Michael Krawitz MD, PhD, Evan E. Eichler PhD, Marco Tartaglia PhD, Sébastien Küry DVM, PhD, Tianyun Wang PhD

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引用次数: 0

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 2025;97:76–89

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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.