Genetic Variants in Craniofacial Dystonias

颅面肌张力障碍的遗传变异

基本信息

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
项目类别：
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

项目摘要

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道路新的治疗方法。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。