Dystonia is a common disorder, mainly seen by neurologists, and defined as a syndrome of involuntary, sustained muscle contractions affecting one or more sites of the body, frequently causing twisting and repetitive movements, or abnormal postures. Dystonia is classified by etiology, age of onset and anatomical distribution. Cervical dystonia, also known as spasmodic torticollis, is the most common type of focal dystonia, affecting over a million persons worldwide. Genetic factors play a major role in late-onset primary dystonia since approximately 10% of probands have one or more affected family members. Using linkage and haplotype analyses in combination with solution-based whole-exome capture and massively parallel sequencing, we identified CIZ1 mutations in some patients with cervical dystonia. CIZ1 encodes Cip1- interacting zinc finger protein 1, a DNA replication factor. CIZ1 was first recognized through its interaction with p21Cip1/Waf1, a cyclin-dependent kinase inhibitor involved in G1/S cell-cycle regulation and cellular differentiation. The cellular role and neural localization of CIZ1 are compatible with current themes in dystonia research. Our global hypothesis is that cervical dystonia is a neurodegenerative disorder of cerebellar Purkinje cells due to defects in G1/S cell-cycle progression. Our first objective is to determine if CIZ1 mutations are specific to cervical dystonia? Semiconductor-based targeted sequencing will be used to examine coding and non-coding regions of CIZ1 in our entire biorepository of dystonia specimens and matching controls. This objective has important clinical implications in the context of genetic testing. Our second objective is to determine the molecular and cellular consequences of identified mutations in CIZ1. In particular, we will determine the effects of CIZ1 mutations on G1/S cell-cycle progression, interaction with other G1/S cell-cycle proteins, and overall gene expression. Our third objective is to interrogate the systems biology of CIZ1 using a collection of knockout and transgenic mouse model systems to control the temporal and spatial expression of wild-type and mutant CIZ1. Finally, the effects of targeted therapeutics will be explored in these models using identifiable motor and/or morphological endpoints. Completion of these objectives will (1) exponentially increase our understanding of dystonia pathogenesis, (2) unify cellular and molecular themes in dystonia research, (3) facilitate etiological diagnoses in patients with primary dystonia, (5) provide systems-level data to support advances in neuromodulatory treatments for dystonia, and (6) provide a solid foundation for cell-cycle targeted intervention in patients with dystonia.

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Dystonia is a common disorder of the nervous system that manifests as prolonged muscle contractions leading to abnormal postures of the face, neck, trunk and limbs. Mutations in the CIZ1 gene cause dystonia that affects the neck muscles. Our research will attempt to determine exactly how CIZ1 mutations cause dystonia.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Clinical Neuroscience and Neurodegeneration Study Section (CNN)
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Sieber, Beth-Anne
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University of Tennessee Health Science Center
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