PUBLICATION
Comparative analysis and functional mapping of SACS mutations reveal novel insights into sacsin repeated architecture
- Authors
- Romano, A., Tessa, A., Barca, A., Fattori, F., de Leva, M.F., Terracciano, A., Storelli, C., Santorelli, F.M., Verri, T.
- ID
- ZDB-PUB-250206-24
- Date
- 2013
- Source
- Human Mutation 34: 525537525-37 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Sequence Alignment
- Muscle Spasticity/genetics*
- Heat-Shock Proteins/genetics*
- Heat-Shock Proteins/metabolism
- Phenotype
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Mutation
- Phylogeny
- Spinocerebellar Ataxias/congenital*
- Spinocerebellar Ataxias/genetics
- Chromosome Mapping*
- Exons
- Humans
- Computational Biology
- Sequence Analysis, DNA
- Polymorphism, Single Nucleotide
- PubMed
- 23280630 Full text @ Hum. Mutat.
Citation
Romano, A., Tessa, A., Barca, A., Fattori, F., de Leva, M.F., Terracciano, A., Storelli, C., Santorelli, F.M., Verri, T. (2013) Comparative analysis and functional mapping of SACS mutations reveal novel insights into sacsin repeated architecture. Human Mutation. 34:525537525-37.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping