SACS Gene: Sacsin Function, Mutations, and ARSACS Disease | NCBI, UniProt, OMIM

The SACS gene encodes sacsin, a large protein (over 520 kDa) that functions as a molecular chaperone involved in mitochondrial dynamics, cytoskeletal organization, and protein quality control. Mutations in SACS cause autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), a neurodegenerative disorder characterized by early-onset spasticity, ataxia, and peripheral neuropathy. Sacsin contains a DnaJ domain, HEPN domain, and a ubiquitin-like domain, suggesting roles in protein folding and stress response.

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• Protein processing in endoplasmic reticulum (KEGG: hsa04141)

• Mitochondrial protein import (Reactome: R-HSA-1268020)

• Chaperone-mediated protein folding (Reactome: R-HSA-390466)

Sacsin is a large multidomain protein (4,579 amino acids) with a DnaJ domain at the N-terminus, a HEPN domain, and a C-terminal ubiquitin-like domain. It acts as a molecular chaperone, facilitating protein folding and mitochondrial homeostasis. Sacsin localizes to mitochondria and interacts with intermediate filaments (e.g., vimentin, GFAP). Loss of sacsin leads to mitochondrial fragmentation, impaired oxidative phosphorylation, and accumulation of protein aggregates, particularly in Purkinje cells of the cerebellum, explaining the neurodegenerative phenotype of ARSACS.