Blackburn Patrick R, Ebstein Frédéric, Hsieh Tzung-Chien, Motta Marialetizia, Radio Francesca Clementina, Herkert Johanna C, Rinne Tuula, Thiffault Isabelle, Rapp Michele, Alders Mariel, Maas Saskia, Gerard Bénédicte, Smol Thomas, Vincent-Delorme Catherine, Cogné Benjamin, Isidor Bertrand, Vincent Marie, Bachmann-Gagescu Ruxandra, Rauch Anita, Joset Pascal, Ferrero Giovanni Battista, Ciolfi Andrea, Husson Thomas, Guerrot Anne-Marie, Bacino Carlos, Macmurdo Colleen, Thompson Stephanie S, Rosenfeld Jill A, Faivre Laurence, Mau-Them Frederic Tran, Deb Wallid, Vignard Virginie, Agrawal Pankaj B, Madden Jill A, Goldenberg Alice, Lecoquierre François, Zech Michael, Prokisch Holger, Necpál Ján, Jech Robert, Winkelmann Juliane, Koprušáková Monika Turčanová, Konstantopoulou Vassiliki, Younce John R, Shinawi Marwan, Mighton Chloe, Fung Charlotte, Morel Chantal F, Lerner-Ellis Jordan, DiTroia Stephanie, Barth Magalie, Bonneau Dominique, Krapels Ingrid, Stegmann Alexander P A, van der Schoot Vyne, Brunet Theresa, Bußmann Cornelia, Mignot Cyril, Zampino Giuseppe, Wortmann Saskia B, Mayr Johannes A, Feichtinger René G, Courtin Thomas, Ravelli Claudia, Keren Boris, Ziegler Alban, Hasadsri Linda, Pichurin Pavel N, Klee Eric W, Grand Katheryn, Sanchez-Lara Pedro A, Krüger Elke, Bézieau Stéphane, Klinkhammer Hannah, Krawitz Peter Michael, Eichler Evan E, Tartaglia Marco, Küry Sébastien, Wang Tianyun
Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.
Institute of Medical Biochemistry and Molecular Biology, University Medicine Greifswald, Greifswald, Germany.
Ann Neurol. 2024 Sep 20. doi: 10.1002/ana.27077.
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.
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.
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.
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.
泛素连接酶cullin-3（CUL3）中的新生变异与神经发育障碍（NDDs）密切相关，但目前尚未有大型病例系列报道。在此，我们旨在收集携带CUL3罕见变异的散发病例，描述基因型-表型相关性，并探究潜在的致病机制。
通过多中心合作收集遗传数据和详细的临床记录。使用GestaltMatcher分析面部畸形特征。使用患者来源的T细胞评估变异对CUL3蛋白稳定性的影响。
我们组建了一个队列，其中37名个体携带杂合CUL3变异，表现为伴有或不伴有自闭症特征的智力障碍综合征性NDD。其中，35个为功能丧失（LoF）变异，2个为错义变异。患者中的CUL3 LoF变异可能影响蛋白质稳定性，导致蛋白质稳态紊乱，体外泛素-蛋白质缀合物减少证明了这一点。值得注意的是，我们发现CUL3的一个主要底物4E-BP1（EIF4EBP1）在患者来源的细胞中未能被靶向蛋白酶体降解。
我们的研究进一步细化了CUL3相关NDDs的临床和突变谱，扩展了cullin RING E3连接酶相关神经精神障碍的谱，表明通过LoF变异导致的单倍体不足是主要的致病机制。《神经病学纪事》2024年。
