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Updated: Jan 21, 2026
In Vitro Analysis of E3 Ubiquitin Ligase Function
Published on: May 14, 2021
Recessive variants in WSB2 encoding a substrate receptor of E3 ubiquitin ligase underlie a neurodevelopmental
Shiyu Luo1,2,3, Valérie Gailus-Durner4, Bobbi McGivern5
1Division of Neonatology, Department of Pediatrics, University of Miami Miller School of Medicine and Holtz Children's Hospital, Jackson Health System, Miami, FL, 33136, USA.
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.
Insights
Loss-of-function variants in WSB2 cause a novel neurodevelopmental disorder in humans. Homozygous mutations in WSB2 lead to developmental delays, brain abnormalities, and neurological issues, mirroring findings in Wsb2-mutant mice.
Area of Science:
- Genetics
- Neuroscience
- Molecular Biology
Background:
- WD40 and SOCS box protein-2 (WSB2) is a substrate receptor for the cullin 5 E3 ligase.
- WSB2 plays a role in proteomic regulation via ubiquitination and proteasomal degradation.
Purpose of the Study:
- To identify the genetic cause of a novel neurodevelopmental disorder.
- To investigate the function of WSB2 in neurological development.
Main Methods:
- Whole-exome sequencing in five patients from four families with neurodevelopmental delay.
- Analysis of homozygous predicted loss-of-function (pLoF) or missense variants in WSB2.
- Phenotypic characterization of Wsb2-mutant mouse models.
Main Results:
- Five patients presented with neurodevelopmental delay, dysmorphic features, brain abnormalities, hypotonia, and microcephaly.
- All patients were homozygous for rare pLoF or missense variants in WSB2.
- Wsb2-mutant mice showed hyperactivity, altered exploration, hyper alertness, reduced weight, bradycardia, and retinal vascular abnormalities.
Conclusions:
- Homozygous loss-of-function WSB2 variants cause a novel human neurodevelopmental disorder.
- The human disorder shares neurological and developmental phenotypes with Wsb2-mutant mice.
- WSB2 is crucial for normal neurodevelopment and systemic regulation.
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