Genetic Variants in Craniofacial Dystonias

项目概要/摘要 在颅面疾病的许多原因中，有局灶性肌张力障碍，如眼睑痉挛（BSP）和 口下颌肌张力障碍（OMD），分别影响眼睛和下颌，以及Meige综合征， 结合了两者的特点。肌张力障碍是激动剂和拮抗剂肌肉的收缩，导致异常 受影响的身体部位的姿势和运动。颅面肌张力障碍知之甚少， 有限的治疗选择。这项拟议中的研究与公共卫生有关，因为了解原因 肌张力障碍，干扰视觉和交流，将有助于指出发展的道路， 新疗法 我们推测颅面肌张力障碍（CFD）可能是由罕见和常见的遗传变异引起的。到 鉴定单基因变异，我们将用CFD对多重家族进行全外显子组测序。评估 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，然后将这些与来自CFD患者的疾病相关成像特征相关联， 识别可能驱动大脑连接改变的基因网络。为了探索的功能效果 识别出突变后，我们将使用基因组编辑工具将它们敲入iPSC系并分析它们的定位 以及神经细胞中蛋白质与蛋白质的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，我们也将用于表征新的颅面疾病变异 通过我们的遗传学和成像分析鉴定。

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.