DNAJB6 Gene - Structure, Function, and Clinical Significance

DNAJB6 encodes a member of the DnaJ/Hsp40 family of co-chaperones, which regulate Hsp70 chaperone activity and are critical for protein folding, degradation, and prevention of aggregation. The protein contains a conserved J-domain that mediates interaction with Hsp70s. Alternative splicing produces two major isoforms: the nuclear/cytoplasmic isoform (DNAJB6a) and the nuclear isoform (DNAJB6b). Mutations in DNAJB6 cause autosomal dominant limb-girdle muscular dystrophy type D1 (LGMDD1), characterized by progressive proximal muscle weakness and myofibrillar pathology with protein aggregates.

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• Hsp70 chaperone cycle (Reactome: R-HSA-3371568)

• Protein processing in endoplasmic reticulum (KEGG: hsa04141)

• Cellular response to heat stress (Reactome: R-HSA-3371556)

DNAJB6 is a 36 kDa co-chaperone with a conserved N-terminal J-domain, a glycine/phenylalanine-rich region, and a C-terminal domain. It binds to Hsp70 via its J-domain, stimulating ATPase activity and facilitating substrate transfer. DNAJB6 is particularly important in muscle cells, where it prevents aggregation of Z-disk proteins such as filamin C and myotilin. Mutations in the J-domain cause LGMDD1 by a dominant-negative mechanism, leading to myofibrillar disorganization and inclusion bodies. The protein is widely expressed, with highest levels in testis and skeletal muscle.