Affiliations 

  • 1 Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan. mnakashi@hama-med.ac.jp
  • 2 Department of Pediatrics, Showa University School of Medicine, Tokyo, Japan
  • 3 Department of Pediatric Neurology, Fukuoka Children's Hospital, Fukuoka, Japan
  • 4 Genetic Department, Hospital Kuala Lumpur, Kuala Lumpur, Malaysia
  • 5 Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands
  • 6 Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan
  • 7 Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan
  • 8 Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan. naomat@yokohama-cu.ac.jp
J Hum Genet, 2020 Sep;65(9):727-734.
PMID: 32341456 DOI: 10.1038/s10038-020-0758-2

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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.