title: Are interrupted SCA2 CAG repeat expansions responsible for parkinsonism?
abstract: BACKGROUND
  Autosomal dominant parkinsonism (ADP) is caused in a large percentage of familial and sporadic cases by mutations in the LRRK2 gene, particularly G2019S. It is also caused by mutations in genes associated with autosomal dominant cerebellar ataxia (ADCA), notably CAG/CAA repeat expansions in SCA2.
  
  
  METHODS
  We screened 164 families with ADP for expansions in the SCA2, 3, and 17 genes and for the G2019S mutation in LRRK2. The SCA2 CAG/CAA repeat expansion was sequenced to determine its structure. The phenotypes of patients with ADP caused by the SCA2, LRRK2, and unknown mutations were compared, as well as those of SCA2 patients with interrupted or uninterrupted expansions of the same size.
  
  
  RESULTS
  Three French ADP families had SCA2 mutations. The expansions ranged from 37 to 39 repeats and were interrupted and stable upon transmission. All patients (n = 9) had levodopa-responsive parkinsonism without cerebellar signs. They had significantly more symmetric signs and less rigidity than ADP caused by the G2019S mutation in LRRK2 or by unknown mutations. Interestingly, two sisters carrying both the SCA2 and the G2019S LRRK2 mutations had markedly earlier onset than their mother with only SCA2. In contrast, similar-sized but uninterrupted repeats were associated with ADCA in which cerebellar ataxia was constant and associated only rarely with one or more mild parkinsonian signs.
  
  
  CONCLUSIONS
  These results suggest that the configuration of the SCA2 CAG/CAA repeat expansions plays an important role in phenotype variability. Uninterrupted SCA2 repeat expansions found in families with autosomal dominant cerebellar ataxia result in somatic mosaicism and produce large hairpin RNAs, which may interact with double-stranded RNA-binding proteins. These characteristics are modified by interruption of the SCA2 repeat expansion as found in families with autosomal dominant parkinsonism.
authors.affiliation: AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Genetics and Cytogenetics, Paris, France.
authors.forename: P
authors.initials: P
authors.lastname: Charles
authors.forename: A
authors.initials: A
authors.lastname: Camuzat
authors.forename: N
authors.initials: N
authors.lastname: Benammar
authors.forename: F
authors.initials: F
authors.lastname: Sellal
authors.forename: A
authors.initials: A
authors.lastname: Destée
authors.forename: A-M
authors.initials: AM
authors.lastname: Bonnet
authors.forename: S
authors.initials: S
authors.lastname: Lesage
authors.forename: I
authors.initials: I
authors.lastname: Le Ber
authors.forename: G
authors.initials: G
authors.lastname: Stevanin
authors.forename: A
authors.initials: A
authors.lastname: Dürr
authors.forename: A
authors.initials: A
authors.lastname: Brice
mesh_terms: D000368:Aged; D000067528:Ataxins; D042622:DNA Repeat Expansion / Q000235:genetics*; D005260:Female; D005602:France / Q000453:epidemiology; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010300:Parkinson Disease / Q000453:epidemiology* / Q000235:genetics*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D015995:Prevalence; D012091:Repetitive Sequences, Nucleic Acid / Q000235:genetics*; D018570:Risk Assessment / Q000379:methods*; D012307:Risk Factors
chemical_list: D000067528:Ataxins; D009419:Nerve Tissue Proteins