title: Comparative analysis and functional mapping of SACS mutations reveal novel insights into sacsin repeated architecture.
abstract: 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.
authors.affiliation: Department of Biological and Environmental Sciences and Technologies, University of Salento, Lecce, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Romano
authors.forename: Alessandra
authors.initials: A
authors.lastname: Tessa
authors.forename: Amilcare
authors.initials: A
authors.lastname: Barca
authors.forename: Fabiana
authors.initials: F
authors.lastname: Fattori
authors.forename: Maria Fulvia
authors.initials: MF
authors.lastname: de Leva
authors.forename: Alessandra
authors.initials: A
authors.lastname: Terracciano
authors.forename: Carlo
authors.initials: C
authors.lastname: Storelli
authors.forename: Filippo Maria
authors.initials: FM
authors.lastname: Santorelli
authors.forename: Tiziano
authors.initials: T
authors.lastname: Verri
mesh_terms: D002874:Chromosome Mapping; D019295:Computational Biology; D005091:Exons; D006360:Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D009128:Muscle Spasticity / Q000235:genetics*; D009154:Mutation; D010641:Phenotype; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D020754:Spinocerebellar Ataxias / Q000151:congenital* / Q000235:genetics
chemical_list: D006360:Heat-Shock Proteins; D012333:RNA, Messenger; C404403:SACS protein, human