DNAJC5 Gene: Function, Mutations, and Associated Diseases (ANCL) | NCBI, UniProt, ClinVar

The DNAJC5 gene encodes cysteine string protein alpha (CSPα), a member of the DnaJ/Hsp40 family of co-chaperones. CSPα is highly expressed in neurons and localizes to synaptic vesicles, where it regulates synaptic vesicle exocytosis, neurotransmitter release, and protects against protein aggregation. Mutations in DNAJC5 cause autosomal dominant adult-onset neuronal ceroid lipofuscinosis (ANCL, also known as CLN4B), a neurodegenerative disorder characterized by progressive myoclonus, seizures, and dementia. The protein contains a J-domain that stimulates the ATPase activity of Hsp70 chaperones, a cysteine-rich string region for palmitoylation and membrane anchoring, and a C-terminal domain involved in vesicle trafficking.

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• Chaperone-mediated protein folding (Hsp70/Hsp40 system)

• Synaptic vesicle cycle

• Protein processing in endoplasmic reticulum

CSPα (DNAJC5) is a 198-amino acid co-chaperone of the Hsp40 family, containing an N-terminal J-domain, a central cysteine-string domain (palmitoylated for membrane tethering), and a C-terminal region. It binds to Hsp70 via its J-domain to stimulate ATP hydrolysis, facilitating protein folding and preventing aggregation. CSPα is essential for synaptic vesicle exocytosis and neurotransmitter release. Mutations in the J-domain cause adult-onset neuronal ceroid lipofuscinosis (ANCL) through a dominant-negative mechanism, leading to progressive neurodegeneration.