Genetic Variants in Craniofacial Dystonias

颅面肌张力障碍的遗传变异

• 批准号: 10686185
• 负责人: NUTAN SHARMA
• 金额: $ 60.18万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10686185
• 关键词: Address; Affect; Agonist; Automobile Driving; Binding; Biological Assay; Blepharospasm; Body part; Brain; Brain Mapping; Brain imaging; Cell Line; Cell model; Cellular biology; Clustered Regularly Interspaced Short Palindromic Repeats; Communication; Complex; DNA analysis; Data; Dependence; Development; Disease; Dystonia; Engineering; Etiology; Eye; Family; Focal Dystonias; Functional Magnetic Resonance Imaging; Genetic; Genetic Risk; Genetic Variation; Genetic study; Genome; Heritability; Human; Image; Individual; Inherited; Investigation; Jaw; Link; Meige Syndrome; Methods; Movement; Muscle; Mutation; National Institute of Dental and Craniofacial Research; Neurons; Nuclear Envelope; Optics; Outcome Study; Pathogenicity; Patients; Pattern; Phenotype; Posture; Proteins; Public Health; Qualifying; Quality of life; Rare Diseases; Records; Research; Research Personnel; Rest; Risk; Risk Factors; Spastic Dysphonias; Syndrome; Testing; Variant; Vision; antagonist; brain cell; clinical phenotype; craniofacial; craniofacial development; craniofacial disorder; disability; disorder risk; exome sequencing; fluorescence lifetime imaging; gene discovery; gene network; genetic analysis; genetic variant; genome editing; genome wide association study; genome-wide; induced pluripotent stem cell; innovation; insight; interest; microscopic imaging; nerve stem cell; neural; neuroimaging; polygenic risk score; protein complex; protein protein interaction; reconstruction; response; segregation; stem cell model; superresolution microscopy; tool; trait

Project Summary/Abstract Among the many causes of craniofacial disease are focal dystonias such as blepharospasm (BSP) and oromandibular dystonia (OMD), affecting the eyes and jaw, respectively, as well as Meige Syndrome, which combines features of both. Dystonia is the contraction of agonist and antagonist muscles, that result in abnormal postures and movement of the affected body parts. Craniofacial dystonias are poorly understood and have limited treatment options. The proposed research is relevant to public health because understanding the causes of dystonia, that interferes with vision and communication, will help to point the way toward the development of new treatment. We hypothesize that craniofacial dystonia (CFD) may be caused by both rare and common genetic variants. To identify monogenic variants, we will perform whole exome sequencing of multiplex families with CFD. To assess the contribution of common variants to CFD, we will use genome-wide association data to compute polygenic risk scores and then correlate these with disease-related imaging signatures derived from CFD patients to identify gene networks that may be driving the altered brain connectivity. To probe the functional effects of identified mutations, we will knock them into iPSC lines using genome editing tools and analyze their localizations and protein:protein interactions in neural cells as initial readouts of their pathogenic potential. These analyses will establish a cellular platform which we will also use for characterizing new craniofacial disease variants identified by our combined genetics and imaging analyses.

项目摘要/摘要 颅面疾病的许多原因包括局灶性肌张力障碍，例如骨痉挛（BSP）和 眼颌骨肌张力障碍（OMD），分别影响眼睛和下巴，以及Meige综合征， 结合了两者的功能。肌张力障碍是激动剂和拮抗剂肌肉的收缩，导致异常 受影响身体部位的姿势和运动。颅面肌肌张力纳斯很了解，并且 有限的治疗选择。拟议的研究与公共卫生有关，因为了解原因 干扰视力和沟通的肌张力障碍将有助于指向发展的道路 新疗法。 我们假设颅面肌张力障碍（CFD）可能是由罕见和常见的遗传变异引起的。到 确定单基因变异，我们将对具有CFD的多重家族进行整个外显子组测序。评估 普通变体对CFD的贡献，我们将使用全基因组关联数据来计算多基因 风险评分，然后将它们与CFD患者衍生的疾病相关的成像特征相关联 确定可能正在推动大脑连通性改变的基因网络。探测 确定的突变，我们将使用基因组编辑工具将其撞到IPSC线上并分析其本地化 和蛋白质：神经细胞中的蛋白质相互作用，作为其致病潜力的初始读数。这些分析 将建立一个蜂窝平台，我们还将用于表征新的颅面疾病变体 通过我们的遗传学和成像分析确定。