Genetic Variants in Craniofacial Dystonias

项目摘要/摘要 分别影响眼睛和下巴的口颌骨肌张力障碍(OMD)，以及Meige综合征，后者 结合了两者的功能。肌张力障碍是激动性和拮抗性肌肉的收缩，导致异常 受影响的身体部位的姿势和运动。颅面肌张力障碍知之甚少。 治疗选择有限。这项拟议的研究与公共健康相关，因为了解原因 肌张力障碍会干扰视力和沟通，这将有助于为发展指明方向 新疗法。 我们假设颅面肌张力障碍(CFD)可能由罕见和常见的遗传变异引起。至 为了确定单基因变异，我们将使用CFD对多基因家族进行完整的外显子组测序。评估 风险评分，然后将这些与CFD患者得出的疾病相关成像特征相关联，以 找出可能驱动大脑连接改变的基因网络。为了探讨其功能效应， 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 将建立一个细胞平台，我们也将利用该平台来表征新的头面部疾病变异 通过我们结合的遗传学和成像分析来鉴定。

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.