Molecular characteristics

Individuals with homozygous or compound heterozygous mutations usually present ARSACS.

Molecular characteristics: In individuals affected by ARSACS, the SACS gene carries missense, nonsense, or frameshift mutations leading to impaired coding for sacsin, a gigantic 520 kDa multi-domain protein. The sacsin protein is ubiquitously expressed but is enriched in the cytoplasm of neurons and dermal fibroblasts. In silico analysis using sequence homology identified the multi-domain organization of sacsin suggests roles in protein chaperoning and protein quality control pathways. Sacsin contains a ubiquitin-like domain (UBL) in the N-terminus with suggested roles in regulating protein degradation by binding to the proteasome 20S. Three large sacsin internal repeat regions (SIRPT1,2,3) unique to sacsin contain heat shock protein (HSP) 90-like domains carrying chaperone activity. A weak homology sequence to XPC-binding domain, which plays a role in DNA damage discrimination and in the enhancement of cell survival is also identified. Finally, a co-chaperone J domain (SacsJ) and a single higher eukaryote and prokaryote nucleotide-binding domain (HEPN) are located in the C-terminus.

Suspected pathophysiologic mechanism: Lack of sacsin causes intermediate filament bundling which has been used as a biomarker for the disease and as a molecular target for therapies development. Intermediate filaments accumulates in dendrites, synases are affected, proteostasis is compromised and lead to neuronal degeneration.

The diagnosis of ARSACS is established in a proband with suggestive clinical findings and biallelic pathogenic variants in SACS identified by molecular genetic testing.