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.
| Original language | English |
|---|---|
| Pages (from-to) | 525-537 |
| Number of pages | 13 |
| Journal | Human Mutation |
| Volume | 34 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - Mar 2013 |
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Keywords
- 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)
Cite this
Comparative Analysis and Functional Mapping of SACS Mutations Reveal Novel Insights into Sacsin Repeated Architecture. / Romano, Alessandro; Tessa, Alessandra; Barca, Amilcare; Fattori, Fabiana; Fulvia de Leva, Maria; Terracciano, Alessandra; Storelli, Carlo; Santorelli, Filippo Maria; Verri, Tiziano.
In: Human Mutation, Vol. 34, No. 3, 03.2013, p. 525-537.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Comparative Analysis and Functional Mapping of SACS Mutations Reveal Novel Insights into Sacsin Repeated Architecture
AU - Romano, Alessandro
AU - Tessa, Alessandra
AU - Barca, Amilcare
AU - Fattori, Fabiana
AU - Fulvia de Leva, Maria
AU - Terracciano, Alessandra
AU - Storelli, Carlo
AU - Santorelli, Filippo Maria
AU - Verri, Tiziano
PY - 2013/3
Y1 - 2013/3
N2 - 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.
AB - 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.
KW - Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS)
KW - Comparative protein analysis
KW - Functional mapping of human mutations
KW - Neurodegeneration
KW - Protein domain architecture
KW - Repeated domains
KW - SACS
KW - Sacsin
UR - http://www.scopus.com/inward/record.url?scp=84873956070&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84873956070&partnerID=8YFLogxK
U2 - 10.1002/humu.22269
DO - 10.1002/humu.22269
M3 - Article
C2 - 23280630
AN - SCOPUS:84873956070
VL - 34
SP - 525
EP - 537
JO - Human Mutation
JF - Human Mutation
SN - 1059-7794
IS - 3
ER -