Adult-Onset Walking-Upstairs Dystonia.
Ontology highlight
ABSTRACT:
SUBMITTER: Portaro S
PROVIDER: S-EPMC6325365 | biostudies-literature | 2019 Jan
REPOSITORIES: biostudies-literature
Publications
Adult-Onset Walking-Upstairs Dystonia.
Portaro Simona S Naro Antonino A Cacciola Alberto A Marra Angela A Quartarone Angelo A Milardi Demetrio D Calabrò Rocco Salvatore RS
Journal of clinical neurology (Seoul, Korea) 20181025 1
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Project description:ObjectivePrimary 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.MethodsLinkage 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.ResultsExome 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).InterpretationMutations 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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