DNAJC3 Gene: Function, Mutations, and Associated Diseases

DNAJC3 encodes a member of the DnaJ/Hsp40 family of co-chaperones, localized to the endoplasmic reticulum (ER). It acts as an inhibitor of the ER-resident kinase PERK (EIF2AK3), thereby modulating the unfolded protein response (UPR). Loss-of-function mutations in DNAJC3 cause a syndrome of diabetes mellitus, neurodegeneration, and growth retardation. The protein is also known as P58IPK due to its ability to inhibit the double-stranded RNA-activated protein kinase PKR.

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• Unfolded Protein Response (UPR) - PERK pathway

• ER stress response

• Protein processing in endoplasmic reticulum (KEGG: hsa04141)

DNAJC3 (P58IPK) is a 504-amino acid co-chaperone localized to the ER lumen. It contains a J-domain that interacts with Hsp70 chaperones and a tetratricopeptide repeat (TPR) domain. Its primary function is to inhibit PERK and PKR kinases, thereby attenuating the UPR and antiviral responses. Loss of DNAJC3 leads to unchecked PERK signaling, chronic eIF2α phosphorylation, and translational attenuation, resulting in beta-cell failure and neurodegeneration.