Journal
ANNALS OF NEUROLOGY
Volume 71, Issue 4, Pages 458-469Publisher
WILEY
DOI: 10.1002/ana.23547
Keywords
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Categories
Funding
- Neuroscience Institute
- Dystonia Medical Research Foundation
- National Institutes of Health (NIH) [R01NS048458, R01NS069936, U54NS065701]
- NIH National Institutes of Neurological Disorders and Stroke (NINDS) [P30NS05710, 1RC2NS070276]
- Clinical Sciences Translation Award [RR024992]
- American Parkinson's Disease Association (APDA) Advanced Research Center
- Greater St Louis Chapter of the APDA
- Barnes-Jewish Hospital Foundation
- Missouri Chapter of the Dystonia Medical Research Foundation
- Murphy Fund
- NIH NINDS Morris K. Udall Center of Excellence [P50NS072187]
- NINDS [NS057567]
- Mayo Clinic Florida Research Committee CR [MCF 90052030]
- BMBF-NGFNplus (German Research Ministry)
- DFG (German Research Foundation)
- NIH Office of Rare Diseases Research [NS067501]
- MJ Fox Foundation
- Huntington Disease Society of America
- Express Scripts
- Bander Foundation for Medical Business Ethics
- Cure HD Initiative
- McDonnell Center for Higher Brain Function
- University of Louisville
- Toronto Western University
- University of Maryland
- American Academy of Neurology
- Korean Movement Disorders Society
- European Union
- BMBF
- Merz
- Teva Neuroscience
- Lundbeck
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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. ANN NEUROL 2012; 71: 458-469
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