Mutations in CIZ1 cause adult onset primary cervical dystonia
Version of Record online: 23 MAR 2012
Copyright © 2012 American Neurological Association
Annals of Neurology
Volume 71, Issue 4, pages 458–469, April 2012
How to Cite
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. and LeDoux, M. S. (2012), Mutations in CIZ1 cause adult onset primary cervical dystonia. Ann Neurol., 71: 458–469. doi: 10.1002/ana.23547
- Issue online: 20 APR 2012
- Version of Record online: 23 MAR 2012
- Accepted manuscript online: 1 FEB 2012 07:20AM EST
- Manuscript Accepted: 27 JAN 2012
- Manuscript Revised: 17 JAN 2012
- Manuscript Received: 9 AUG 2011
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.
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.
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 p21Cip1/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).
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. ANN NEUROL 2012