Mutation in CUL4B, which encodes a member of cullin-RING ubiquitin ligase complex, causes X-linked mental retardation

Am J Hum Genet. 2007 Mar;80(3):561-6. doi: 10.1086/512489. Epub 2007 Jan 25.


We reevaluated a previously reported family with an X-linked mental retardation syndrome and attempted to identify the underlying genetic defect. Screening of candidate genes in a 10-Mb region on Xq25 implicated CUL4B as the causative gene. CUL4B encodes a scaffold protein that organizes a cullin-RING (really interesting new gene) ubiquitin ligase (E3) complex in ubiquitylation. A base substitution, c.1564C-->T, converted a codon for arginine into a premature termination codon, p.R388X, and rendered the truncated peptide completely devoid of the C-terminal catalytic domain. The nonsense mutation also results in nonsense-mediated mRNA decay in patients. In peripheral leukocytes of obligate carriers, a strong selection against cells expressing the mutant allele results in an extremely skewed X-chromosome inactivation pattern. Our findings point to the functional significance of CUL4B in cognition and in other aspects of human development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / genetics*
  • Adolescent
  • Adult
  • Child
  • Child, Preschool
  • Chromosomes, Human, X / genetics*
  • Cullin Proteins / genetics*
  • Dosage Compensation, Genetic
  • Female
  • Genetic Linkage
  • Humans
  • Male
  • Mental Retardation, X-Linked / genetics*
  • Mutation / genetics*
  • Pedigree


  • CUL4B protein, human
  • Cullin Proteins

Associated data

  • RefSeq/NM_003588