Comparative Analysis and Functional Mapping of SACS Mutations Reveal Novel Insights into Sacsin Repeated Architecture

Alessandro Romano, Alessandra Tessa, Amilcare Barca, Fabiana Fattori, Maria Fulvia de Leva, Alessandra Terracciano, Carlo Storelli, Filippo Maria Santorelli, Tiziano Verri

Research output: Contribution to journalArticlepeer-review


Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a neurological disease with mutations in SACS, encoding sacsin, a multidomain protein of 4,579 amino acids. The large size of SACS and its translated protein has hindered biochemical analysis of ARSACS, and how mutant sacsins lead to disease remains largely unknown. Three repeated sequences, called sacsin repeating region (SRR) supradomains, have been recognized, which contribute to sacsin chaperone-like activity. We found that the three SRRs are much larger (≥1,100 residues) than previously described, and organized in discrete subrepeats. We named the large repeated regions Sacsin Internal RePeaTs (SIRPT1, SIRPT2, and SIRPT3) and the subrepeats sr1, sr2, sr3, and srX. Comparative analysis of vertebrate sacsins in combination with fine positional mapping of a set of human mutations revealed that sr1, sr2, sr3, and srX are functional. Notably, the position of the pathogenic mutations in sr1, sr2, sr3, and srX appeared to be related to the severity of the clinical phenotype, as assessed by defining a severity scoring system. Our results suggest that the relative position of mutations in subrepeats will variably influence sacsin dysfunction. The characterization of the specific role of each repeated region will help in developing a comprehensive and integrated pathophysiological model of function for sacsin.

Original languageEnglish
Pages (from-to)525-537
Number of pages13
JournalHuman Mutation
Issue number3
Publication statusPublished - Mar 2013


  • Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS)
  • Comparative protein analysis
  • Functional mapping of human mutations
  • Neurodegeneration
  • Protein domain architecture
  • Repeated domains
  • SACS
  • Sacsin

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


Dive into the research topics of 'Comparative Analysis and Functional Mapping of SACS Mutations Reveal Novel Insights into Sacsin Repeated Architecture'. Together they form a unique fingerprint.

Cite this