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

• 批准号: 8853347
• 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
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8853347
• 关键词: Accounting; Adult; Adult-Onset Dystonias; Affect; Age of Onset; Area; Biological Models; Biology; CDKN1A gene; Caucasians; 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 disorder; Gene Expression; Genes; Genetic; Genetic screening method; Genetic study; Genome; Gliosis; Haplotypes; Health; 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; Untranslated RNA; Variant; Zinc Fingers; base; biobank; exome; follow-up; gain of function; genetic pedigree; insertion/deletion mutation; loss of function; mouse model; mutant; nervous system disorder; neuroregulation; next generation; proband; relating to nervous system; screening; targeted sequencing; therapeutic target

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（申请人提供）：肌张力障碍是一种常见疾病，主要由神经科医生就诊，定义为影响身体一个或多个部位的不自主、持续肌肉收缩的综合征，经常导致扭曲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。颈部肌张力障碍，也称为痉挛性斜颈，是最常见的局灶性肌张力障碍类型，影响全世界超过一百万人。遗传因素在迟发性原发性肌张力障碍中起主要作用，因为大约10%的先证者有一个或多个受影响的家庭成员。 使用连锁和单体型分析，结合基于溶液的全外显子组捕获和大规模平行测序，我们确定了一些宫颈肌张力障碍患者的CIZ 1突变。CIZ 1编码Cip 1相互作用锌指蛋白1，一种DNA复制因子。CIZ 1首先通过与p21 Cip 1/Waf 1相互作用而被识别，p21 Cip 1/Waf 1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。的 CIZ 1的细胞作用和神经定位与肌张力障碍研究中的当前主题是一致的。我们的总体假设是，颈部肌张力障碍是小脑浦肯野细胞的神经退行性疾病，由于G1/S细胞周期进展的缺陷。 我们的首要目标是 确定CIZ 1突变是否特异于宫颈肌张力障碍？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的生物储存库中CIZ 1的编码和非编码区。这一目标在基因检测方面具有重要的临床意义。我们的第二个目标是确定CIZ 1中已鉴定突变的分子和细胞后果。特别是，我们将确定CIZ 1突变对G1/S细胞周期进程的影响，与其他G1/S细胞周期蛋白的相互作用，以及整体基因表达。我们的第三个目标是询问CIZ 1的系统生物学，使用一系列敲除和转基因小鼠模型系统来控制野生型和突变型CIZ 1的时空表达。最后，将在这些模型中使用可识别的运动和/或形态学终点探索靶向治疗的效果。 这些目标的完成将（1）以指数方式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中的细胞和分子主题，（3）促进原发性肌张力障碍患者的病因诊断，（5）提供系统水平的数据，以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坚实的基础。