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Luo, S.* ; Gailus-Durner, V. ; McGivern, B.* ; Li, Q.* ; Kottmeier, J.* ; Ho, M.L.* ; Mor-Shaked, H.* ; Elpeleg, O.* ; Aref-Eshghi, E.* ; Brodeur, A.C.* ; Schmitz-Abe, K.* ; Genetti, C.A.* ; Picker, J.* ; Shi, J.* ; Bux, R.I.* ; Ben-Omran, T.* ; Fuchs, H. ; Harel, T.* ; Hrabě de Angelis, M. ; German Mouse Clinic Consortium (Garrett, L. ; Amarie, O.V. ; Spielmann, N. ; Sanz-Moreno, A. ; da Silva Buttkus, P. ; Becker, L. ; Hölter, S. ; Seisenberger, C. ; Marschall, S.) ; German Mouse Clinic Consortium (Dragano, N.R.V.) ; German Mouse Clinic Consortium (Aguilar-Pimentel, J.A.)

Recessive variants in WSB2 encoding a substrate receptor of E3 ubiquitin ligase underlie a neurodevelopmental syndrome.

Eur. J. Hum. Genet., DOI: 10.1038/s41431-025-01863-4 (2025)
Verlagsversion Forschungsdaten DOI PMC
Open Access Hybrid
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WD40 and SOCS box protein-2 (WSB2), a member of the large family of suppressor of cytokine signaling (SOCS)-box proteins, has recently been identified as a substrate receptor of cullin 5 E3 ligase that plays an important role in proteomic regulation through substrate ubiquitination and proteasomal degradation. Here we report five patients from four unrelated families presenting with neurodevelopmental delay, dysmorphic features, brain structural abnormalities with or without growth restriction, hypotonia, and microcephaly, all of whom are homozygous for extremely rare and predicted loss-of-function (pLoF) or missense variants in WSB2, inherited from consanguineous parents. The Wsb2-mutant mice exhibited several neurological findings that included hyperactivity, altered exploration, and hyper alertness. They also weighed less, had a lower heart rate, and presented an abnormal retinal blood vessel morphology and vasculature pattern along with decreased total thickness of the retina. Our findings suggest that homozygous LoF WSB2 variants cause a novel neurodevelopmental disorder in humans with similar neurologic and developmental findings seen in Wsb2-mutant mouse models.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Neurogenesis; Protein; Dysfunction; Mutations; Promotes
Sprache englisch
Veröffentlichungsjahr 2025
HGF-Berichtsjahr 2025
ISSN (print) / ISBN 1018-4813
e-ISSN 1476-5438
Zeitschrift European Journal of Human Genetics
Verlag Nature Publishing Group
Verlagsort Campus, 4 Crinan St, London, N1 9xw, England
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Experimental Genetics (IEG)
POF Topic(s) 30201 - Metabolic Health
Forschungsfeld(er) Genetics and Epidemiology
PSP-Element(e) G-500600-001
G-500692-001
Förderungen Because of Bella Foundation, Batchelor Foundation
DOI 10.1038/s41431-025-01863-4
WOS ID 001489014200001
Scopus ID 105005408654
PubMed ID 40374945
Erfassungsdatum 2025-05-20
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