Omics · study · 2026
The HEPN domain of SACSIN binds to RNA
Listed in NCBI GEO
Autosomal Recessive Spastic Ataxia of Charlevoix–Saguenay (ARSACS) is a neurodegenerative disorder caused by mutations on the SACS gene, though the molecular function of its protein product, SACSIN, remains elusive.
Description
Therapeutic strategies for ARSACS are limited, mostly due to the exceptionally large size of SACSIN (~520 kDa), which precludes conventional gene therapy and standard molecular delivery methods. Over 200 pathogenic variants, including missense and nonsense mutations, have been identified.
Regardless of the variant type, patients uniformly exhibit cerebellar ataxia and spasticity. Among them, patients carrying missense mutations within the SACSIN higher eukaryotes and prokaryotes nucleotide-binding (HEPN) domain. Thus, suggesting that the alteration of the functional role of SACSIN HEPN domain can be linked to the manifestation of ARSACS symptoms.
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Here, we provide the first direct evidence that SACSIN HEPN domain binds to RNA, corroborating the hypothesis that SACSIN functions as an RNA-binding protein. In silico predictions through the catRAPID algorithm as well as AlphaFold 3.0 revealed the propensity of SACSIN HEPN domain to specifically interact with RNAs sharing a conserved GC-rich structured motif. These interactions were validated both in vitro as well as in cell studies, overall confirming that SACSIN HEPN domain binds to RNA transcripts.
Finally, we identified by APEX-Seq the RNA transcripts bound by SACSIN HEPN domain in cells. Overall, our study unveils an unknown molecular function of SACSIN that, if altered, can contribute to the development of ARSACS disease.
Links
Get the data
- GEO FTP directory ftp.ncbi.nlm.nih.gov/geo/series/GSE312nnn/GSE312176 ↗
download · from NCBI GEO
Where it is published
- GEO accession page ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE312176 ↗
landing page · from NCBI GEO
Documentation and papers
- PRJNA1372603 ncbi.nlm.nih.gov/bioproject/PRJNA1372603 ↗
project · from NCBI GEO
Topics
- Stated by source
- Expression profiling by high throughput sequencing · Homo sapiens
- From keywords
- Life Sciences
- Inferred from text
- Disease 75%
Provenance · 1 source records, 8 field assertions
| Source | Key | Last seen | Raw |
|---|---|---|---|
| NCBI GEO | GSE312176 | 13 d ago | JSON v1 |
| Field | Assertion | Extractor | Evidence |
|---|---|---|---|
| access_level | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[disease].local:disease:disease | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (75%) |
| concepts[field].local:field:life-sciences | mapping · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[method].geo_series_type:expression-profiling-by-high-throughput-sequencing | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /gdstype |
| concepts[organism].NCBITaxon:9606 | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /taxon |
| description | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /summary |
| publication_date | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| title | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /title |