A mental retardation-linked nonsense mutation in cereblon is rescued by proteasome inhibition.

A nonsense mutation in cereblon (CRBN) causes autosomal recessive  nonsyndromic mental retardation. Cereblon is a substrate receptor for  the Cullin-RING E3 ligase complex and couples the ubiquitin ligase to  specific ubiquitination targets. The CRBN nonsense mutation (R419X)  results in a protein lacking 24 amino acids at its C terminus. Although  this mutation has been linked to mild mental retardation, the mechanism  by which the mutation affects CRBN function is unknown. Here, we used  biochemical and mass spectrometric approaches to explore the function of  this mutant. We show that the protein retains its ability to assemble  into a Cullin-RING E3 ligase complex and catalyzes the ubiquitination of  CRBN-target proteins. However, we find that this mutant exhibits  markedly increased levels of autoubiquitination and is more readily  degraded by the proteasome than the wild type protein. We also show that  the level of the mutant protein can be restored by a treatment of cells  with a clinically utilized proteasome inhibitor, suggesting that this  agent may be useful for the treatment of mental retardation associated  with the CRBN R419X mutation. These data demonstrate that enhanced  autoubiquitination and degradation account for the defect in CRBN  activity that leads to mental retardation.