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：
8631382
负责人：
MARK S LEDOUX
金额：
$ 32.81万
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/8631382
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 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疾病，主要由神经科医生发现，定义为影响身体一个或多个部位的不自主、持续的肌肉收缩的综合征，经常引起扭转和重复运动或异常姿势。肌张力障碍根据病因、发病年龄和解剖分布进行分类。颈肌肌张力障碍，也称为痉挛性斜颈，是局灶性肌张力障碍的最常见类型，影响全球超过一百万人。遗传因素在迟发性原发性肌张力障碍中发挥着重要作用，因为大约 10% 的先证者有一名或多名受影响的家庭成员。通过使用连锁和单倍型分析，结合基于解决方案的全外显子组捕获和大规模并行测序，我们在一些颈部肌张力障碍患者中发现了 CIZ1 突变。 CIZ1 编码与 Cip1 相互作用的锌指蛋白 1，一种 DNA 复制因子。 CIZ1 首次通过与 p21Cip1/Waf1 的相互作用而被认识，p21Cip1/Waf1 是一种参与 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。这 CIZ1 的细胞作用和神经定位与肌张力障碍研究的当前主题相一致。我们的总体假设是，颈肌张力障碍是一种由于 G1/S 细胞周期进展缺陷而导致的小脑浦肯野细胞的神经退行性疾病。我们的首要目标是确定 CIZ1 突变是否特定于颈肌肌张力障碍？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生物样本库和匹配对照中 CIZ1 的编码和非编码区域。这一目标在基因检测背景下具有重要的临床意义。我们的第二个目标是确定 CIZ1 中已识别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、与其他 G1/S 细胞周期蛋白的相互作用以及整体基因表达的影响。我们的第三个目标是使用一系列敲除和转基因小鼠模型系统来探究 CIZ1 的系统生物学，以控制野生型和突变型 CIZ1 的时间和空间表达。最后，将使用可识别的运动和/或形态学终点在这些模型中探索靶向治疗的效果。完成这些目标将（1）成倍增加我们对肌张力障碍发病机制的理解，（2）统一肌张力障碍研究的细胞和分子主题，（3）促进原发性肌张力障碍患者的病因诊断，（5）提供系统级数据来支持肌张力障碍神经调节治疗的进展，以及（6）为肌张力障碍患者的细胞周期靶向干预提供了坚实的基础。