Genetics and Biology of CIZ1 in Cervical Dystonia

CIZ1 在宫颈肌张力障碍中的遗传学和生物学

基本信息

批准号：
8734493
负责人：
MARK S LEDOUX
金额：
$ 32.48万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-15 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8734493
关键词：
Accounting Adult Adult-Onset Dystonias Affect Age of Onset Area Biological Models Biology CDKN1A gene Caucasians Caucasoid Race Cell Cycle Cell Cycle Progression Cell Cycle Proteins Cell Cycle Regulation Cell Death Cerebellar cortex structure Cerebellum Cervical Dystonia Childhood Clinical Code Collection Cyclin-Dependent Kinase Inhibitor DNA Replication Factor Data Defect Development Diagnosis Disease Dopa-Responsive Dystonia Drug Formulations Dystonia Etiology Face Family member Focal Dystonias Foundations Functional RNA Functional disorder Gene Expression Genes Genetic Genetic screening method Genome Gliosis Haplotypes Human Human Genetics Individual Intervention Knock-out Knockout Mice Life Limb structure Link Massive Parallel Sequencing Medical Research Modeling Molecular Molecular Target Molecular and Cellular Biology Motor Movement Mus Muscle Contraction Mutation Neck Neurobiology Neurodegenerative Disorders Neurologist Nuclear Pathogenesis Patients Penetrance Persons Phenotype Play Posture Primary Dystonias Proteins Publications Publishing Purkinje Cells Reporting Research Role Semiconductors Seminal Site Skeletal muscle structure of neck Solid Solutions Spasmodic torticollis Specimen Sporadic Dystonias Structure Syndrome System Systems Biology TAF1 gene TOR1A gene Therapeutic Intervention Tissues Torpedo Transcript Transgenic Mice Variant Zinc Fingers base biobank exome follow-up gain of function genetic pedigree loss of function mouse model mutant nervous system disorder next generation proband public health relevance relating to nervous system screening therapeutic target

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：肌张力障碍是一种常见的疾病，主要由神经科医生看，定义为一种非自愿，持续的肌肉收缩综合征，影响人体一个或多个部位，经常引起扭曲和重复运动，或者是异常的姿势。肌张力障碍由病因，发作年龄和解剖分布进行分类。宫颈肌张力障碍，也被称为痉挛性核桃，是最常见的局灶性肌张力障碍类型，影响了全球超过一百万的人。遗传因素在晚期原发性肌张力障碍中起主要作用，因为大约10％的概率具有一个或多个受影响的家庭成员。使用链接和单倍型分析与溶液基于溶液的全外观捕获和大量平行测序结合使用，我们确定了一些宫颈肌张力障碍患者的CIZ1突变。 CIZ1编码CIP1-相互作用的锌指蛋白1，DNA复制因子。 CIZ1首先通过与P21CIP1/WAF1的相互作用（一种涉及G1/S细胞周期调节和细胞分化的细胞周期蛋白依赖性激酶抑制剂）的相互作用来识别。这 CIZ1的细胞作用和神经定位与肌张力障碍研究中的当前主题兼容。我们的全球假设是，由于G1/S细胞周期进展中缺陷，宫颈肌张力障碍是小脑Purkinje细胞的神经退行性疾病。我们的第一个目标是确定CIZ1突变是否针对宫颈肌张力障碍？基于半导体的靶向测序将用于检查我们整个肌张力障碍标本和匹配对照组的CIZ1中CIZ1的编码和非编码区域。该目标在基因检测的背景下具有重要的临床意义。我们的第二个目标是确定CIZ1中鉴定突变的分子和细胞后果。特别是，我们将确定CIZ1突变对G1/S细胞周期进展的影响，与其他G1/S细胞周期蛋白的相互作用以及总体基因表达。我们的第三个目标是使用敲除和转基因小鼠模型系统的集合来询问CIZ1的系统生物学，以控制野生型和突变体CIZ1的时间和空间表达。最后，将使用可识别的电动机和/或形态学终点探索靶向治疗剂的效果。这些目标的完成将（1）指数增强我们对肌肌张力障碍发病机理的理解，（2）在肌张力障碍研究中统一细胞和分子主题，（（3）促进原发性障碍患者的病因诊断，（5）提供系统水平的数据，以支持降低型肌张力障碍和（6）的基础（6）的构造，并提供肌张力障碍（6）。肌张力障碍。