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DOI 10.1002/ana.27077

Медицинская библиотека · Annals of neurology · 2024

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

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

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Аннотация

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.

Для цитирования: 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. Loss-of-Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder.. Annals of neurology. 2024. DOI: 10.1002/ana.27077.
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