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

Patrick R. Blackburn; Frederic Ebstein; Tzung-Chien Hsieh; Marialetizia Motta; Francesca Clementina Radio; Johanna C. Herkert; Tuula Rinne; Isabelle Thiffault; Michele Rapp; Mariel Alders; Saskia Maas; Benedicte Gerard; Thomas Smol; Catherine Vincent-Delorme; Benjamin Cogne; 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; Francois Lecoquierre; Michael Zech; Holger Prokisch; Jan Necpal; Robert Jech; Juliane Winkelmann; Monika Turcanova Koprusakova; 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; Rene 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 Krueger; Stephane Bezieau; Hannah Klinkhammer; Peter Michael Krawitz; Evan E. Eichler; Marco Tartaglia; Sebastien Kuery; Tianyun Wang

doi:10.1002/ana.27077

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

Patrick R. Blackburn, Frederic Ebstein, Tzung-Chien Hsieh, Marialetizia Motta, Francesca Clementina Radio, Johanna C. Herkert, Tuula Rinne, Isabelle Thiffault, Michele Rapp, Mariel Alders, Saskia Maas, Benedicte Gerard, Thomas Smol, Catherine Vincent-Delorme, Benjamin Cogne, 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, Francois Lecoquierre, Michael Zech, Holger Prokisch, Jan Necpal, Robert Jech, Juliane Winkelmann, Monika Turcanova Koprusakova, 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 (Co-author), Johannes A. Mayr (Co-author), Rene G. Feichtinger (Co-author), Thomas Courtin, Claudia Ravelli, Boris Keren, Alban Ziegler, Linda Hasadsri, Pavel N. Pichurin, Eric W. Klee, Katheryn Grand, Pedro A. Sanchez-Lara, Elke Krueger, Stephane Bezieau, Hannah Klinkhammer, Peter Michael Krawitz, Evan E. Eichler, Marco Tartaglia, Sebastien Kuery, Tianyun Wang

Department of Pediatrics

Research output: Contribution to journal › Original Article › peer-review

Abstract

Purpose:<bold> </bold>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:<bold> </bold>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:<bold> </bold>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	14
Journal	ANNALS OF NEUROLOGY
Early online date	Sept 2024
DOIs	https://doi.org/10.1002/ana.27077
Publication status	Published - 20 Sept 2024

Keywords

De-novo mutations
Protein network
Cullin 3
Subunit
Genes
Phenotype
Encodes

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10.1002/ana.27077

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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., Cogne, B., Isidor, B., Vincent, M., Bachmann-Gagescu, R., Rauch, A., ... Wang, T. (2024). Loss-of-Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder. ANNALS OF NEUROLOGY https://doi.org/10.1002/ana.27077

Blackburn, Patrick R. ; Ebstein, Frederic ; Hsieh, Tzung-Chien et al. / Loss-of-Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder. In: ANNALS OF NEUROLOGY 2024.

@article{994afd6a0fa14defbff8ac2f40f82e3d,

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.",

keywords = "De-novo mutations, Protein network, Cullin 3, Subunit, Genes, Phenotype, Encodes",

author = "Blackburn, {Patrick R.} and Frederic 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 Benedicte Gerard and Thomas Smol and Catherine Vincent-Delorme and Benjamin Cogne 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 Francois Lecoquierre and Michael Zech and Holger Prokisch and Jan Necpal and Robert Jech and Juliane Winkelmann and Koprusakova, {Monika Turcanova} and Vassiliki Konstantopoulou and Younce, {John R.} and Marwan Shinawi and Chloe Mighton and Charlotte Fung and Morel, {Chantal F.} and Jordan Lerner-Ellis and Stephanie Ditroia and Magalie Barth and Dominique Bonneau and Ingrid Krapels and Stegmann, {Alexander P. A.} and {van Der Schoot}, Vyne and Theresa Brunet and Cornelia Bussmann and Cyril Mignot and Giuseppe Zampino and Wortmann, {Saskia B.} and Mayr, {Johannes A.} and Feichtinger, {Rene G.} 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 Krueger and Stephane Bezieau and Hannah Klinkhammer and Krawitz, {Peter Michael} and Eichler, {Evan E.} and Marco Tartaglia and Sebastien Kuery and Tianyun Wang",

note = "Wortmann, Mayr, Feichtinger: University Children{\textquoteright}s Hospital, Paracelsus Medical University (PMU), Salzburg, Austria",

year = "2024",

month = sep,

day = "20",

doi = "10.1002/ana.27077",

language = "English",

journal = "ANNALS OF NEUROLOGY ",

issn = "0364-5134",

publisher = "Wiley Verlag ",

}

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, Cogne, 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, Necpal, J, Jech, R, Winkelmann, J, Koprusakova, MT, Konstantopoulou, V, Younce, JR, Shinawi, M, Mighton, C, Fung, C, Morel, CF, Lerner-Ellis, J, Ditroia, S, Barth, M, Bonneau, D, Krapels, I, Stegmann, APA, van Der Schoot, V, Brunet, T, Bussmann, C, Mignot, C, Zampino, G, Wortmann, SB , Mayr, JA , Feichtinger, RG, Courtin, T, Ravelli, C, Keren, B, Ziegler, A, Hasadsri, L, Pichurin, PN, Klee, EW, Grand, K, Sanchez-Lara, PA, Krueger, E, Bezieau, S, Klinkhammer, H, Krawitz, PM, Eichler, EE, Tartaglia, M, Kuery, S & Wang, T 2024, 'Loss-of-Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder', ANNALS OF NEUROLOGY https://doi.org/10.1002/ana.27077

Loss-of-Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder. / Blackburn, Patrick R.; Ebstein, Frederic; Hsieh, Tzung-Chien et al.
In: ANNALS OF NEUROLOGY , 20.09.2024.

Research output: Contribution to journal › Original Article › peer-review

TY - JOUR

T1 - Loss-of-Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder

AU - Blackburn, Patrick R.

AU - Ebstein, Frederic

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, Benedicte

AU - Smol, Thomas

AU - Vincent-Delorme, Catherine

AU - Cogne, 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, Francois

AU - Zech, Michael

AU - Prokisch, Holger

AU - Necpal, Jan

AU - Jech, Robert

AU - Winkelmann, Juliane

AU - Koprusakova, Monika Turcanova

AU - Konstantopoulou, Vassiliki

AU - Younce, John R.

AU - Shinawi, Marwan

AU - Mighton, Chloe

AU - Fung, Charlotte

AU - Morel, Chantal F.

AU - Lerner-Ellis, Jordan

AU - Ditroia, Stephanie

AU - Barth, Magalie

AU - Bonneau, Dominique

AU - Krapels, Ingrid

AU - Stegmann, Alexander P. A.

AU - van Der Schoot, Vyne

AU - Brunet, Theresa

AU - Bussmann, Cornelia

AU - Mignot, Cyril

AU - Zampino, Giuseppe

AU - Wortmann, Saskia B.

AU - Mayr, Johannes A.

AU - Feichtinger, Rene G.

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 - Krueger, Elke

AU - Bezieau, Stephane

AU - Klinkhammer, Hannah

AU - Krawitz, Peter Michael

AU - Eichler, Evan E.

AU - Tartaglia, Marco

AU - Kuery, Sebastien

AU - Wang, Tianyun

N1 - Wortmann, Mayr, Feichtinger: University Children’s Hospital, Paracelsus Medical University (PMU), Salzburg, Austria

PY - 2024/9/20

Y1 - 2024/9/20

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.

KW - De-novo mutations

KW - Protein network

KW - Cullin 3

KW - Subunit

KW - Genes

KW - Phenotype

KW - Encodes

UR - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=pmu_pure&SrcAuth=WosAPI&KeyUT=WOS:001317007900001&DestLinkType=FullRecord&DestApp=WOS_CPL

U2 - 10.1002/ana.27077

DO - 10.1002/ana.27077

M3 - Original Article

C2 - 39301775

SN - 0364-5134

JO - ANNALS OF NEUROLOGY

JF - ANNALS OF NEUROLOGY

ER -

Blackburn PR, Ebstein F, Hsieh TC, Motta M, Radio FC, Herkert JC et al. Loss-of-Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder. ANNALS OF NEUROLOGY . 2024 Sept 20. Epub 2024 Sept. doi: 10.1002/ana.27077

Loss-of-Function Variants in <i>CUL3</i> Cause a Syndromic Neurodevelopmental Disorder

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