Genetics and Biology of CIZ1 in Cervical Dystonia

描述（由申请人提供）：肌张力障碍是一种常见疾病，主要由神经科医生治疗，定义为一种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，经常引起扭曲和重复运动，或异常姿势。肌张力障碍按病因、发病年龄和解剖分布进行分类。颈肌张力障碍，也被称为痉挛性斜颈，是局灶性肌张力障碍最常见的类型，影响着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。通过连锁和单倍型分析，结合基于溶液的全外显子组捕获和大规模平行测序，我们在一些宫颈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，这是一种DNA复制因子。CIZ1最初是通过与p21Cip1/Waf1相互作用而被发现的，p21Cip1/Waf1是一种周期蛋白依赖性激酶抑制剂，参与G1/S细胞周期调节和细胞分化。这个

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.