• Open Access

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


  • Communicated by David N. Cooper

  • Contract grant sponsors: University of Salento (fondi ex-60% 2009–2012); Italian Ministry of Health; Telethon Italy (GGP10121A).

Correspondence to: Filippo M. Santorelli, Molecular Medicine and Neurogenetics, Children Neuropsychiatry Institute, University of Pisa, IRCCS Fondazione Stella Maris, Viale del Tirreno 331, I-56018 Pisa, Italy. E-mail: filippo3364@gmail.com or Tiziano Verri, Laboratory of General Physiology, Department of Biological and Environmental Sciences and Technologies, University of Salento, Via Provinciale Lecce-Monteroni, I-73100 Lecce, Italy. E-mail: tiziano.verri@unisalento.it


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.