Abstract

Autosomal recessive spastic ataxia of CharlevoixSaguenay (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.

Autore Pugliese

• Verri Tiziano

Tutti gli autori

• A. Romano , A. Tessa , A. Barca , F. Fattori , M.F. de Leva , A. Terracciano , C. Storelli , F.M.Santorelli , T. Verri

Titolo volume/Rivista

HUMAN MUTATION

Anno di pubblicazione

2013

ISSN

1059-7794

ISBN

Non Disponibile

Numero di citazioni Wos

8

Ultimo Aggiornamento Citazioni

28/04/2018

Numero di citazioni Scopus

9

Ultimo Aggiornamento Citazioni

28/04/2018

Settori ERC

Non Disponibile

Codici ASJC

Non Disponibile