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 Ledoux

Research output: Contribution to journalArticle

103 Citations (Scopus)

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). 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
Volume71
Issue number4
DOIs
StatePublished - Apr 1 2012

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Dystonic Disorders
Mutation
Exome
Torticollis
Zinc Fingers
High-Throughput Nucleotide Sequencing
Missense Mutation
Pedigree
Cell Cycle Checkpoints
Haplotypes
Exons
Cell Cycle
Proteins
Central Nervous System
Primary Cervical Dystonia
DNA
Brain
Genes

All Science Journal Classification (ASJC) codes

  • Neurology
  • Clinical Neurology

Cite this

Xiao, J., Uitti, R. J., Zhao, Y., Vemula, S. R., Perlmutter, J. S., Wszolek, Z. K., ... Ledoux, M. (2012). Mutations in CIZ1 cause adult onset primary cervical dystonia. Annals of Neurology, 71(4), 458-469. https://doi.org/10.1002/ana.23547

Mutations in CIZ1 cause adult onset primary cervical dystonia. / Xiao, Jianfeng; Uitti, Ryan J.; Zhao, Yu; Vemula, Satya R.; Perlmutter, Joel S.; Wszolek, Zbigniew K.; Maraganore, Demetrius M.; Auburger, Georg; Leube, Barbara; Lehnhoff, Katja; Ledoux, Mark.

In: Annals of Neurology, Vol. 71, No. 4, 01.04.2012, p. 458-469.

Research output: Contribution to journalArticle

Xiao, J, Uitti, RJ, Zhao, Y, Vemula, SR, Perlmutter, JS, Wszolek, ZK, Maraganore, DM, Auburger, G, Leube, B, Lehnhoff, K & Ledoux, M 2012, 'Mutations in CIZ1 cause adult onset primary cervical dystonia', Annals of Neurology, vol. 71, no. 4, pp. 458-469. https://doi.org/10.1002/ana.23547
Xiao J, Uitti RJ, Zhao Y, Vemula SR, Perlmutter JS, Wszolek ZK et al. Mutations in CIZ1 cause adult onset primary cervical dystonia. Annals of Neurology. 2012 Apr 1;71(4):458-469. https://doi.org/10.1002/ana.23547
Xiao, Jianfeng ; Uitti, Ryan J. ; Zhao, Yu ; Vemula, Satya R. ; Perlmutter, Joel S. ; Wszolek, Zbigniew K. ; Maraganore, Demetrius M. ; Auburger, Georg ; Leube, Barbara ; Lehnhoff, Katja ; Ledoux, Mark. / Mutations in CIZ1 cause adult onset primary cervical dystonia. In: Annals of Neurology. 2012 ; Vol. 71, No. 4. pp. 458-469.
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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). 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.",
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AU - Wszolek, Zbigniew K.

AU - Maraganore, Demetrius M.

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AU - Ledoux, Mark

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N2 - 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.

AB - 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.

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