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De novo variants in CUL3 are associated with global developmental delays with or without infantile spasms
Mitsuko Nakashima1,2, Mitsuhiro Kato3, Masaru Matsukura4
1Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan. mnakashi@hama-med.ac.jp.
Abstract:
The ubiquitin-proteasome system is the principal system for protein degradation mediated by ubiquitination and is involved in various cellular processes. Cullin-RING ligases (CRL) are one class of E3 ubiquitin ligases that mediate polyubiquitination of specific target proteins, leading to decomposition of the substrate. Cullin 3 (CUL3) is a member of the Cullin family proteins, which act as scaffolds of CRL. Here we describe three cases of global developmental delays, with or without epilepsy, who had de novo CUL3 variants. One missense variant c.854T>C, p.(Val285Ala) and two frameshift variants c.137delG, p.(Arg46Leufs*32) and c.1239del, p.(Asp413Glufs*42) were identified by whole-exome sequencing. The Val285 residue located in the Cullin N-terminal domain and p.Val285Ala CUL3 mutant showed significantly weaker interactions to the BTB domain proteins than wild-type CUL3. Our findings suggest that de novo CUL3 variants may cause structural instability of the CRL complex and impairment of the ubiquitin-proteasome system, leading to diverse neuropsychiatric disorders.
Insights
New genetic variants in the CUL3 gene are linked to global developmental delays and epilepsy. These de novo CUL3 variants disrupt the ubiquitin-proteasome system, potentially causing neurodevelopmental disorders.
Area of Science:
- Genetics
- Molecular Biology
- Neuroscience
Background:
- The ubiquitin-proteasome system (UPS) is crucial for cellular protein degradation.
- Cullin-RING ligases (CRLs) are key E3 ubiquitin ligases within the UPS.
- Cullin 3 (CUL3) acts as a scaffold protein in CRL complexes.
Observation:
- Three individuals with global developmental delays and epilepsy presented with de novo CUL3 variants.
- Identified variants include one missense (p.Val285Ala) and two frameshift (p.Arg46Leufs*32, p.Asp413Glufs*42) mutations.
- The p.Val285Ala CUL3 mutant exhibited reduced interaction with BTB domain proteins.
Findings:
- De novo CUL3 variants can lead to structural instability of CRL complexes.
- Impairment of the ubiquitin-proteasome system is associated with these CUL3 variants.
- CUL3 dysfunction may underlie diverse neuropsychiatric disorders.
Implications:
- This study highlights CUL3 as a potential genetic cause for developmental disorders.
- Understanding CUL3's role in the UPS offers insights into neurodevelopmental pathogenesis.
- Further research into CUL3 variants could inform diagnostic and therapeutic strategies for related conditions.