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

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 JosetGiovanni 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^*

^*Corresponding author for this work

Research output: Working paper / Preprint › Preprint

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.

Original language	English
Number of pages	37
DOIs	https://doi.org/10.1101/2023.06.13.23290941
Publication status	Published - 16 Jun 2023

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Series	medRxiv : the preprint server for Health Sciences

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10.1101/2023.06.13.23290941

https://www.zora.uzh.ch/id/eprint/234237/1/2023.06.13.23290941.full.pdfLicence: Other

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Blackburn, P. R., Ebstein, F., Hsieh, T.-C., Motta, M., Radio, F. C., Herkert, J. C., 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., ... Wang, T. (2023). Loss-of-function variants in CUL3 cause a syndromic neurodevelopmental disorder. medRxiv : the preprint server for Health Sciences https://doi.org/10.1101/2023.06.13.23290941

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title = "Loss-of-function variants in CUL3 cause a syndromic neurodevelopmental disorder",

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.",

author = "Blackburn, {Patrick R} and Fr{\'e}d{\'e}ric Ebstein and Tzung-Chien Hsieh and Marialetizia Motta and Radio, {Francesca Clementina} and Herkert, {Johanna C} and Tuula Rinne and Isabelle Thiffault and Michele Rapp and Mariel Alders and Saskia Maas and B{\'e}n{\'e}dicte Gerard and Thomas Smol and Catherine Vincent-Delorme and Benjamin Cogn{\'e} and Bertrand Isidor and Marie Vincent and Ruxandra Bachmann-Gagescu and Anita Rauch and Pascal Joset and Ferrero, {Giovanni Battista} and Andrea Ciolfi and Thomas Husson and Anne-Marie Guerrot and Carlos Bacino and Colleen Macmurdo and Thompson, {Stephanie S} and Rosenfeld, {Jill A} and Laurence Faivre and Mau-Them, {Frederic Tran} and Wallid Deb and Virginie Vignard and Agrawal, {Pankaj B} and Madden, {Jill A} and Alice Goldenberg and Fran{\c c}ois Lecoquierre and Michael Zech and Holger Prokisch and J{\'a}n Necp{\'a}l and Robert Jech and Juliane Winkelmann and Kopru{\v s}{\'a}kov{\'a}, {Monika Tur{\v c}anov{\'a}} and Vassiliki Konstantopoulou and Younce, {John R} and Marwan Shinawi and Chloe Mighton and Charlotte Fung and Chantal Morel and Ellis, {Jordan Lerner-} and Stephanie DiTroia and Magalie Barth and Dominique Bonneau and Ingrid Krapels and Sander Stegmann and {van der Schoot}, Vyne and Theresa Brunet and Cornelia Bu{\ss}mann and Cyril Mignot and Thomas Courtin and Claudia Ravelli and Boris Keren and Alban Ziegler and Linda Hasadsri and Pichurin, {Pavel N} and Klee, {Eric W} and Katheryn Grand and Sanchez-Lara, {Pedro A} and Elke Kr{\"u}ger and St{\'e}phane B{\'e}zieau and Hannah Klinkhammer and Krawitz, {Peter Michael} and Eichler, {Evan E} and Marco Tartaglia and S{\'e}bastien K{\"u}ry and Tianyun Wang",

year = "2023",

month = jun,

day = "16",

doi = "10.1101/2023.06.13.23290941",

language = "English",

series = "medRxiv : the preprint server for Health Sciences",

publisher = "Cold Spring Harbor Laboratory - bioRxiv",

type = "WorkingPaper",

institution = "Cold Spring Harbor Laboratory - bioRxiv",

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Blackburn, PR, Ebstein, F, Hsieh, T-C, 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, A-M, 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, C, Ellis, JL, DiTroia, S, Barth, M, Bonneau, D, Krapels, I , Stegmann, S, van der Schoot, V, Brunet, T, Bußmann, C, Mignot, C, 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 2023 'Loss-of-function variants in CUL3 cause a syndromic neurodevelopmental disorder' medRxiv : the preprint server for Health Sciences. https://doi.org/10.1101/2023.06.13.23290941

TY - UNPB

T1 - Loss-of-function variants in CUL3 cause a syndromic neurodevelopmental disorder

AU - Blackburn, Patrick R

AU - Ebstein, Frédéric

AU - Hsieh, Tzung-Chien

AU - Motta, Marialetizia

AU - Radio, Francesca Clementina

AU - Herkert, Johanna C

AU - Rinne, Tuula

AU - Thiffault, Isabelle

AU - Rapp, Michele

AU - Alders, Mariel

AU - Maas, Saskia

AU - Gerard, Bénédicte

AU - Smol, Thomas

AU - Vincent-Delorme, Catherine

AU - Cogné, Benjamin

AU - Isidor, Bertrand

AU - Vincent, Marie

AU - Bachmann-Gagescu, Ruxandra

AU - Rauch, Anita

AU - Joset, Pascal

AU - Ferrero, Giovanni Battista

AU - Ciolfi, Andrea

AU - Husson, Thomas

AU - Guerrot, Anne-Marie

AU - Bacino, Carlos

AU - Macmurdo, Colleen

AU - Thompson, Stephanie S

AU - Rosenfeld, Jill A

AU - Faivre, Laurence

AU - Mau-Them, Frederic Tran

AU - Deb, Wallid

AU - Vignard, Virginie

AU - Agrawal, Pankaj B

AU - Madden, Jill A

AU - Goldenberg, Alice

AU - Lecoquierre, François

AU - Zech, Michael

AU - Prokisch, Holger

AU - Necpál, Ján

AU - Jech, Robert

AU - Winkelmann, Juliane

AU - Koprušáková, Monika Turčanová

AU - Konstantopoulou, Vassiliki

AU - Younce, John R

AU - Shinawi, Marwan

AU - Mighton, Chloe

AU - Fung, Charlotte

AU - Morel, Chantal

AU - Ellis, Jordan Lerner-

AU - DiTroia, Stephanie

AU - Barth, Magalie

AU - Bonneau, Dominique

AU - Krapels, Ingrid

AU - Stegmann, Sander

AU - van der Schoot, Vyne

AU - Brunet, Theresa

AU - Bußmann, Cornelia

AU - Mignot, Cyril

AU - Courtin, Thomas

AU - Ravelli, Claudia

AU - Keren, Boris

AU - Ziegler, Alban

AU - Hasadsri, Linda

AU - Pichurin, Pavel N

AU - Klee, Eric W

AU - Grand, Katheryn

AU - Sanchez-Lara, Pedro A

AU - Krüger, Elke

AU - Bézieau, Stéphane

AU - Klinkhammer, Hannah

AU - Krawitz, Peter Michael

AU - Eichler, Evan E

AU - Tartaglia, Marco

AU - Küry, Sébastien

AU - Wang, Tianyun

PY - 2023/6/16

Y1 - 2023/6/16

N2 - 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.

AB - 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.

U2 - 10.1101/2023.06.13.23290941

DO - 10.1101/2023.06.13.23290941

M3 - Preprint

C2 - 37398376

T3 - medRxiv : the preprint server for Health Sciences

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

ER -

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

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