Genetic Variants in Craniofacial Dystonias

颅面肌张力障碍的遗传变异

• 批准号: 10364887
• 负责人: NUTAN SHARMA
• 金额: $ 61.88万
• 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/10364887
• 关键词: Address; Affect; Agonist; Automobile Driving; Binding; Biological Assay; Blepharospasm; Body part; Brain; 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; Maps; Meige Syndrome; Methods; Microscopy; Movement; Muscle; Mutation; National Institute of Dental and Craniofacial Research; Neurons; Nuclear Envelope; Optics; Outcome Study; Pathogenicity; Patients; Pattern; Phenotype; Posture; Proteins; Public Health; Quality of life; Rare Diseases; Records; Research; Research Personnel; Resolution; 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; nerve stem cell; neuroimaging; polygenic risk score; protein complex; protein protein interaction; reconstruction; relating to nervous system; response; stem cell differentiation; stem cell model; 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.

项目概要/摘要 颅面疾病的众多原因之一是局灶性肌张力障碍，例如眼睑痉挛 (BSP) 和 口下颌肌张力障碍（OMD），分别影响眼睛和下巴，以及梅格综合症， 结合了两者的特点。肌张力障碍是主动肌和拮抗肌的收缩，导致异常 受影响身体部位的姿势和运动。人们对颅面肌张力障碍知之甚少，并且 治疗选择有限。拟议的研究与公共卫生相关，因为了解其原因 肌张力障碍会干扰视力和交流，这将有助于为发展指明方向 新的治疗方法。 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 识别单基因变异后，我们将使用 CFD 对多重家族进行全外显子组测序。评估 由于常见变异对 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，然后将这些评分与来自 CFD 患者的疾病相关成像特征关联起来 识别可能导致大脑连接改变的基因网络。探究功能效果 识别出突变后，我们将使用基因组编辑工具将它们敲入 iPSC 系并分析其定位 神经细胞中的蛋白质：蛋白质相互作用作为其致病潜力的初始读数。这些分析 将建立一个细胞平台，我们也将使用该平台来表征新的颅面疾病变异 通过我们结合遗传学和成像分析确定。