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

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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Publication Details

Journal
European Journal of Human Genetics
Published
2025-05-15
DOI
https://doi.org/10.1038/s41431-025-01863-4
Citations
2
Primary Topic
Ubiquitin and proteasome pathways
Type
article
Field-Weighted Citation Impact
1.61

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article

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

Martin Hrabě de Angelis, Helmut Fuchs, Mai‐Lan Ho, Jonathan Picker et al.
2 citations
European Journal of Human Genetics
Ubiquitin and proteasome pathways
1.61
article

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

Martin Hrabě de Angelis, Helmut Fuchs, Mai‐Lan Ho, Jonathan Picker, Qifei Li, Shiyu Luo, Orly Elpeleg, Reem Ibrahim Bux, Erfan Aref‐Eshghi, Jiahai Shi, Tamar Harel, Klaus Schmitz‐Abe, Hagar Mor‐Shaked, Casie A. Genetti, Tawfeg Ben‐Omran, Valérie Gailus-Durner, Bobbi McGivern, Amanda C Brodeur, Jessica Kottmeier
article en
2 citations

Abstract

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.

European Journal of Human GeneticsVol. 34(1)
Boston Children's Hospital (US), Harvard University (US), University of Miami (US), National University of Singapore (SG), Hebrew University of Jerusalem (IL), Hadassah Medical Center (IL), Helmholtz Zentrum München (DE), Weihenstephan-Triesdorf University of Applied Sciences (DE), Jackson Health System (US), University of Miami Hospital (US), Deutsches Diabetes-Zentrum e.V. (DE), German Center for Diabetes Research (DE), Heinrich Heine University Düsseldorf (DE), Hamad Medical Corporation (QA), Technical University of Munich (DE), University of Missouri (US)
University of Miami, INFRAFRONTIER, Bundesministerium für Bildung und Forschung, Manton Center for Orphan Disease Research, Boston Children's Hospital
Openalex Percentile: Top 17%
Ubiquitin and proteasome pathways
1.61
DOIOpen Access PDFOpenAlex
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