title: Mutations in CIZ1 cause adult onset primary cervical dystonia.
abstract: OBJECTIVE
  Primary dystonia is usually of adult onset, can be familial, and frequently involves the cervical musculature. Our goal was to identify the causal mutation in a family with adult onset, primary cervical dystonia.
  
  
  METHODS
  Linkage and haplotype analyses were combined with solution-based whole-exome capture and massively parallel sequencing in a large Caucasian pedigree with adult onset, primary cervical dystonia to identify a cosegregating mutation. High-throughput screening and Sanger sequencing were completed in 308 Caucasians with familial or sporadic adult onset cervical dystonia and matching controls for sequence variants in this mutant gene.
  
  
  RESULTS
  Exome sequencing led to the identification of an exonic splicing enhancer mutation in exon 7 of CIZ1 (c.790A>G, p.S264G), which encodes CIZ1, Cip1-interacting zinc finger protein 1. CIZ1 is a p21(Cip1/Waf1) -interacting zinc finger protein expressed in brain and involved in DNA synthesis and cell-cycle control. Using a minigene assay, we showed that c.790A>G altered CIZ1 splicing patterns. The p.S264G mutation also altered the nuclear localization of CIZ1. Screening in subjects with adult-onset cervical dystonia identified 2 additional CIZ1 missense mutations (p.P47S and p.R672M).
  
  
  CONCLUSIONS
  Mutations in CIZ1 may cause adult onset, primary cervical dystonia, possibly by precipitating neurodevelopmental abnormalities that manifest in adults and/or G1/S cell-cycle dysregulation in the mature central nervous system.
authors.affiliation: Department of Neurology, University of Tennessee Health Science Center, Memphis, USA.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Xiao
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Uitti
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhao
authors.forename: Satya R
authors.initials: SR
authors.lastname: Vemula
authors.forename: Joel S
authors.initials: JS
authors.lastname: Perlmutter
authors.forename: Zbigniew K
authors.initials: ZK
authors.lastname: Wszolek
authors.forename: Demetrius M
authors.initials: DM
authors.lastname: Maraganore
authors.forename: Georg
authors.initials: G
authors.lastname: Auburger
authors.forename: Barbara
authors.initials: B
authors.lastname: Leube
authors.forename: Katja
authors.initials: K
authors.lastname: Lehnhoff
authors.forename: Mark S
authors.initials: MS
authors.lastname: LeDoux
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D004252:DNA Mutational Analysis; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D010375:Pedigree; D014103:Torticollis / Q000235:genetics*
chemical_list: C400423:Ciz1 protein, human; D009687:Nuclear Proteins