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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.* ; Gérard, B.* ; Smol, T.* ; Vincent-Delorme, C.* ; Cogné, B.* ; Isidor, B.* ; Vincent, M.* ; Bachmann-Gagescu, R.* ; Rauch, A.* ; Joset, P.* ; Ferrero, G.B.* ; Ciolfi, A.* ; Husson, T.* ; Guerrot, A.M.* ; Bacino, C.A.* ; Macmurdo, C.* ; Thompson, S.S.* ; Rosenfeld, J.A.* ; Faivre, L.* ; Mau-them, F.T.* ; Deb, W.* ; Vignard, V.* ; Agrawal, P.B.* ; Madden, J.A.* ; Goldenberg, A.* ; Lecoquierre, F.* ; Zech, M. ; Prokisch, H. ; Necpál, J.* ; Jech, R.* ; Winkelmann, J. ; Koprusakova, M.T.* ; Konstantopoulou, V.* ; Younce, J.R.* ; Shinawi, M.* ; Mighton, C.* ; Fung, C.* ; Morel, C.F.* ; Lerner-Ellis, J.* ; DiTroia, S.* ; Barth, M.* ; Bonneau, D.* ; Krapels, I.P.* ; Stegmann, A.P.A.* ; van der Schoot, V.* ; Brunet, T.* ; Bußmann, C.* ; Mignot, C.* ; Zampino, G.* ; Wortmann, S.B.* ; Mayr, J.A.* ; Feichtinger, R.G.* ; Courtin, T.* ; Ravelli, C.* ; Keren, B.* ; Ziegler, A.* ; Hasadsri, L.* ; Pichurin, P.N.* ; Klee, E.W.* ; Grand, K.* ; Sanchez-Lara, P.A.* ; Krüger, E.* ; Bézieau, S.* ; Klinkhammer, H.* ; Krawitz, P.M.* ; Eichler, E.E.* ; Tartaglia, M.* ; Küry, S.* ; Wang, T.*

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

Ann. Neurol., DOI: 10.1002/ana.27077 (2024)
Verlagsversion DOI PMC
Closed
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter De-novo Mutations; Protein Network; Cullin 3; Subunit; Genes; Phenotype; Encodes
Sprache englisch
Veröffentlichungsjahr 2024
HGF-Berichtsjahr 2024
ISSN (print) / ISBN 0364-5134
e-ISSN 1531-8249
Zeitschrift Annals of Neurology
Verlag Wiley
Verlagsort 111 River St, Hoboken 07030-5774, Nj Usa
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Neurogenomics (ING)
POF Topic(s) 30205 - Bioengineering and Digital Health
Forschungsfeld(er) Genetics and Epidemiology
PSP-Element(e) G-503200-001
G-503292-001
Förderungen Mutuelles AXA
National Institutes of Health (NIH)
Fundamental Research Funds for the Central Universities starting fund
National Natural Science Foundation of China
DOI 10.1002/ana.27077
WOS ID 001317007900001
Scopus ID 85204741826
PubMed ID 39301775
Erfassungsdatum 2024-10-11
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