title: Diversity of ARSACS mutations in French-Canadians.
abstract: BACKGROUND
  The growing number of spastic ataxia of Charlevoix-Saguenay (SACS) gene mutations reported worldwide has broadened the clinical phenotype of autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). The identification of Quebec ARSACS cases without two known SACS mutation led to the development of a multi-modal genomic strategy to uncover mutations in this large gene and explore phenotype variability.
  
  
  METHODS
  Search for SACS mutations by combining various methods on 20 cases with a classical French-Canadian ARSACS phenotype without two mutations and a group of 104 sporadic or recessive spastic ataxia cases of unknown cause. Western blot on lymphoblast protein from cases with different genotypes was probed to establish if they still expressed sacsin.
  
  
  RESULTS
  A total of 12 mutations, including 7 novels, were uncovered in Quebec ARSACS cases. The screening of 104 spastic ataxia cases of unknown cause for 98 SACS mutations did not uncover carriers of two mutations. Compounds heterozygotes for one missense SACS mutation were found to minimally express sacsin.
  
  
  CONCLUSIONS
  The large number of SACS mutations present even in Quebec suggests that the size of the gene alone may explain the great genotypic diversity. This study does not support an expanding ARSACS phenotype in the French-Canadian population. Most mutations lead to loss of function, though phenotypic variability in other populations may reflect partial loss of function with preservation of some sacsin expression. Our results also highlight the challenge of SACS mutation screening and the necessity to develop new generation sequencing methods to ensure low cost complete gene sequencing.
authors.affiliation: Neurogenetics of Motion Laboratory, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.
authors.forename: I
authors.initials: I
authors.lastname: Thiffault
authors.forename: M J
authors.initials: MJ
authors.lastname: Dicaire
authors.forename: M
authors.initials: M
authors.lastname: Tetreault
authors.forename: K N
authors.initials: KN
authors.lastname: Huang
authors.forename: J
authors.initials: J
authors.lastname: Demers-Lamarche
authors.forename: G
authors.initials: G
authors.lastname: Bernard
authors.forename: A
authors.initials: A
authors.lastname: Duquette
authors.forename: R
authors.initials: R
authors.lastname: Larivière
authors.forename: K
authors.initials: K
authors.lastname: Gehring
authors.forename: A
authors.initials: A
authors.lastname: Montpetit
authors.forename: P S
authors.initials: PS
authors.lastname: McPherson
authors.forename: A
authors.initials: A
authors.lastname: Richter
authors.forename: L
authors.initials: L
authors.lastname: Montermini
authors.forename: J
authors.initials: J
authors.lastname: Mercier
authors.forename: G A
authors.initials: GA
authors.lastname: Mitchell
authors.forename: N
authors.initials: N
authors.lastname: Dupré
authors.forename: C
authors.initials: C
authors.lastname: Prévost
authors.forename: J P
authors.initials: JP
authors.lastname: Bouchard
authors.forename: J
authors.initials: J
authors.lastname: Mathieu
authors.forename: B
authors.initials: B
authors.lastname: Brais
mesh_terms: D015331:Cohort Studies; D004252:DNA Mutational Analysis; D004576:Electromyography; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006360:Heat-Shock Proteins / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008297:Male; D009128:Muscle Spasticity / Q000208:ethnology / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D011792:Quebec; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D020754:Spinocerebellar Ataxias / Q000151:congenital* / Q000208:ethnology / Q000235:genetics
chemical_list: D006360:Heat-Shock Proteins; C404403:SACS protein, human