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.

Links

PMC Free PDF

Publisher Full Text

Authors

Xiao J, Uitti RJ, Zhao Y, Vemula SR, Perlmutter JS, Wszolek ZK, Maraganore DM, Auburger G, Leube B, Lehnhoff K, LeDoux MS

Institution

Department of Neurology, University of Tennessee Health Science Center, Memphis, USA.

Source

Annals of neurology 71:4 2012 Apr pg 458-69

MeSH

Adult
Amino Acid Sequence
DNA Mutational Analysis
Female
Genetic Linkage
Genetic Predisposition to Disease
Genotype
Humans
Male
Molecular Sequence Data
Mutation
Nuclear Proteins
Pedigree
Torticollis

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22447717