CRBN Gene: Cereblon - Function, Mutations, and Role in IMiD Therapy

The CRBN gene encodes cereblon, a protein that forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1) and cullin-4A (CUL4A). This complex ubiquitinates target proteins for proteasomal degradation. CRBN is the primary target of thalidomide and its analogs (lenalidomide, pomalidomide), which alter its substrate specificity, leading to degradation of transcription factors such as IKZF1 and IKZF3. Loss-of-function mutations in CRBN cause autosomal recessive non-syndromic intellectual disability (MRT2A).

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• Ubiquitin mediated proteolysis (KEGG: hsa04120)

• CUL4A-DDB1-CRBN E3 ligase complex pathway

Cereblon is a 442-amino acid protein that functions as a substrate receptor in the CUL4A-DDB1-RBX1 E3 ubiquitin ligase complex. It contains a Lon protease-like domain and a thalidomide-binding domain. Binding of immunomodulatory drugs (IMiDs) such as lenalidomide alters the substrate specificity of the complex, leading to ubiquitination and degradation of neosubstrates like IKZF1 and IKZF3. This mechanism underlies the therapeutic effects of IMiDs in multiple myeloma and del(5q) MDS. Loss-of-function mutations cause autosomal recessive intellectual disability (MRT2A).