title: ARSACS, a spastic ataxia common in northeastern Québec, is caused by mutations in a new gene encoding an 11.5-kb ORF.
abstract: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS or SACS) is an early onset neurodegenerative disease with high prevalence (carrier frequency 1/22) in the Charlevoix-Saguenay-Lac-Saint-Jean (CSLSJ) region of Quebec. We previously mapped the gene responsible for ARSACS to chromosome 13q11 and identified two ancestral haplotypes. Here we report the cloning of this gene, SACS, which encodes the protein sacsin. The ORF of SACS is 11,487 bp and is encoded by a single gigantic exon spanning 12,794 bp. This exon is the largest to be identified in any vertebrate organism. The ORF is conserved in human and mouse. The putative protein contains three large segments with sequence similarity to each other and to the predicted protein of an Arabidopsis thaliana ORF. The presence of heat-shock domains suggests a function for sacsin in chaperone-mediated protein folding. SACS is expressed in a variety of tissues, including the central nervous system. We identified two SACSmutations in ARSACS families that lead to protein truncation, consistent with haplotype analysis.
authors.affiliation: Montreal Genome Centre, McGill University Health Centre Research Institute, Montréal, Québec, Canada.
authors.forename: J C
authors.initials: JC
authors.lastname: Engert
authors.forename: P
authors.initials: P
authors.lastname: Bérubé
authors.forename: J
authors.initials: J
authors.lastname: Mercier
authors.forename: C
authors.initials: C
authors.lastname: Doré
authors.forename: P
authors.initials: P
authors.lastname: Lepage
authors.forename: B
authors.initials: B
authors.lastname: Ge
authors.forename: J P
authors.initials: JP
authors.lastname: Bouchard
authors.forename: J
authors.initials: J
authors.lastname: Mathieu
authors.forename: S B
authors.initials: SB
authors.lastname: Melançon
authors.forename: M
authors.initials: M
authors.lastname: Schalling
authors.forename: E S
authors.initials: ES
authors.lastname: Lander
authors.forename: K
authors.initials: K
authors.lastname: Morgan
authors.forename: T J
authors.initials: TJ
authors.lastname: Hudson
authors.forename: A
authors.initials: A
authors.lastname: Richter
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017360:Arabidopsis / Q000235:genetics; D001259:Ataxia / Q000235:genetics*; D001483:Base Sequence; D002874:Chromosome Mapping; D002882:Chromosomes, Human, Pair 13; D005091:Exons; D006360:Heat-Shock Proteins / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D016366:Open Reading Frames; D015995:Prevalence; D011792:Quebec / Q000453:epidemiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013132:Spinocerebellar Degenerations / Q000235:genetics*
chemical_list: D006360:Heat-Shock Proteins; C404403:SACS protein, human; C498616:Sacs protein, mouse