Mutations in CIZ1 cause adult onset primary cervical dystonia

Jianfeng Xiao, Ryan J. Uitti, Yu Zhao, Satya R. Vemula, Joel S. Perlmutter, Zbigniew K Wszolek, Demetrius M. Maraganore, Georg Auburger, Barbara Leube, Katja Lehnhoff, Mark S. Ledoux

Research output: Contribution to journalArticle

108 Scopus citations


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). Interpretation: 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.

Original languageEnglish (US)
Pages (from-to)458-469
Number of pages12
JournalAnnals of Neurology
Issue number4
StatePublished - Apr 2012


ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Xiao, J., Uitti, R. J., Zhao, Y., Vemula, S. R., Perlmutter, J. S., Wszolek, Z. K., Maraganore, D. M., Auburger, G., Leube, B., Lehnhoff, K., & Ledoux, M. S. (2012). Mutations in CIZ1 cause adult onset primary cervical dystonia. Annals of Neurology, 71(4), 458-469.