De novo variants in CUL3 are associated with global developmental delays with or without infantile spasms

J Hum Genet. 2020 Sep;65(9):727-734. doi: 10.1038/s10038-020-0758-2. Epub 2020 Apr 27.


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.

Publication types

  • Case Reports

MeSH terms

  • Child
  • Child, Preschool
  • Cullin Proteins / genetics*
  • Cullin Proteins / metabolism*
  • Developmental Disabilities / complications
  • Developmental Disabilities / genetics*
  • Developmental Disabilities / physiopathology
  • Exome Sequencing
  • Female
  • Frameshift Mutation
  • Genetic Predisposition to Disease*
  • HEK293 Cells
  • Humans
  • Infant
  • Male
  • Mutation, Missense
  • Protein Binding
  • Spasms, Infantile / complications
  • Spasms, Infantile / genetics*
  • Ubiquitin-Protein Ligases / metabolism


  • CUL3 protein, human
  • Cullin Proteins
  • CULL-RING ligase, human
  • Ubiquitin-Protein Ligases