Neurodevelopmental disorders (NDDs), including intellectual disability, epilepsy, and autism, are often caused by disruptions in molecular pathways like ubiquitination, which regulates protein stability. E3 ubiquitin ligases, particularly the Cullin-RING ligases (CRLs), play a key role in these processes, and dozens of E3 ligase-related genes have been linked to various NDDs. WSB2, a SOCS-box protein and suspected substrate receptor (SR) for the Cullin 5-RBX2-Elongin B/C (CRL5) complex, is broadly expressed in tissues, including the brain, but has not previously been associated with human disease. While WSB2 targets proteins such as p53 and cyclin D1, its role in neurodevelopment is unclear.
[Taken from Nature] A Representative schematic of WSB2 gene (NM_018639.5) containing seven WD-repeats and a suppressor of cytokine signaling (SOCS) box in the C-terminus. The WSB2 variants are positioned in WD1, WD2, and SOCS box domain, respectively. B Molecular modeling of WSB2 missense variant (NM_018639.5: c.1121G>A, p.Arg374Gln). As shown in the top panel, the wildtype residue’s (Arg374, red) positively charged side chain interacts with the aromatic rings of Phe398 and Phe404 (shown in blue), helping stabilize this region. In contrast, the side chain of Gln374 (red, bottom panel) forms weaker hydrophobic contacts with these phenylalanine, thereby potentially increasing local flexibility of the SOCS box domain. C Representative magnetic resonance imaging (MRI) of patient 2 with homozygous c.399del p.(Q134Rfs*14) at 12 months of age. (i) Sagittal T1-weighted MRI showing microcephaly, callosal hypogenesis (white arrow), tectal dysplasia (yellow arrow), and severe cerebellar hypoplasia/atrophy (dotted oval). (ii and iii) Axial T1- and T2-weighted MRI show undersulcation and white matter hypomyelination for age. (iv-vi) Coronal T2-weighted with fat suppression show small olfactory bulbs (black arrows), optic nerves (white arrows), and hippocampi (yellow arrows).
This study involved patients identified through collaborative genetic research efforts. Clinical evaluations included detailed phenotyping and pedigree analysis. Exome and genome sequencing were performed using Illumina platforms with variant interpretation supported by Geneyx analysis software. Structural modeling of WSB2 used AlphaFold and PyMOL. A Wsb2 knockout mouse model, generated by the International Knockout Mouse Consortium, underwent extensive phenotyping at the German Mouse Clinic (GMC) in accordance with IMPC standards. Cohorts of mutant and wild-type mice were compared across numerous physiological and behavioral traits.
Through international collaboration, five affected individuals from four unrelated consanguineous families were identified with homozygous variants in the WSB2 gene, including loss-of-function (LOF) or missense mutations. These variants were discovered via exome/genome sequencing and confirmed by Sanger sequencing. Patients with LOF mutations had severe phenotypic traits, including hypotonia, microcephaly, dysmorphic attributes, and brain abnormalities, while cases with the missense variant exhibited milder symptoms. Mouse models carrying the Wsb2 mutation displayed phenotypes overlapping with human patients.
In summary, this study identifies recessive variants in the WSB2 gene as the cause of NDD. WSB2 encodes an SR of the CRL5 E3 ubiquitin ligase complex, important for protein degradation. Mutations in WSB2 are likely to disrupt this process, impairing neurodevelopment. WSB2 is widely expressed in the brain, especially the neocortex, and Wsb2-mutant mice exhibit phenotypes paralleling human patients. Although WSB2 has previously been studied in cancer, this is the first report linking it to a syndromic NDD. Further functional studies are needed to clarify its role and pathogenic mechanisms.
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