Mechanisms of Brain Dysmorphology in MN1 C-Terminal Truncation Syndrome, a Novel Intellectual Developmental Disability Disorder

MN1 C 端截断综合征（一种新型智力发育障碍）的脑形态异常机制

• 批准号: 10085034
• 负责人: DANIEL DOHERTY
• 金额: $ 26.47万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-28 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10085034
• 关键词: Alleles; Animal Behavior; Animal Model; Antisense Oligonucleotides; Behavioral Assay; Brain; Brain imaging; C-terminal; Candidate Disease Gene; Cell Differentiation process; Cell model; Cerebellar malformation; Cerebellar vermis structure; Cerebellum; Cerebral cortex; Characteristics; Collaborations; DNA Sequence; Data; Development; Developmental Brain Malformation; Developmental Disabilities; Disease; Dominant-Negative Mutation; Dysmorphology; Epilepsy; Future; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; High Prevalence; Histology; Human; Individual; Intellectual and Developmental Disabilities Research Centers; Intellectual functioning disability; Investigation; Life; Magnetic Resonance Imaging; Methods; Microgyria; Modeling; Molecular; Morbidity - disease rate; Mus; Neuronal Migration Disorder; Neurons; Nonsense-Mediated Decay; Parents; Pathway interactions; Patients; Phenotype; Proteins; RNA Sequence Analysis; Research Personnel; Research Project Grants; Research Project Summaries; Role; Structure; Syndrome; Testing; Transcript; Transcriptional Regulation; Variant; base; brain malformation; craniofacial; cranium; differential expression; experience; gain of function; gene discovery; human model; human stem cells; insight; microCT; migration; mortality; mouse model; nerve stem cell; novel; single cell sequencing; stem cells; transcription factor; transcriptome sequencing

Project Summary – Research Project The mechanisms underlying Intellectual and Developmental Disabilities (IDDs) remain largely unknown. A substantial number of individuals with IDDs have developmental brain malformations which are associated with considerable morbidity and mortality. This proposal focuses on a newly identified IDD condition (MCTT syndrome), characterized by IDD, epilepsy, characteristic craniofacial differences, and two important brain malformations: polymicrogyria (PMG) and rhombencephalosynapsis (RES). PMG is a common feature in many IDDs and is strongly associated with developmental disability and epilepsy. Although PMG is known to be due to aberrant neuronal migration, the causes and molecular mechanisms remain incompletely understood, and few good animal models exist. RES is a unique cerebellar malformation characterized by fusion of the cerebellar hemispheres with partial or complete absence of a recognizable cerebellar vermis; almost nothing is known about the causes and mechanisms underlying RES, and no animal models exist. This project represents a synergistic collaboration between human and mouse model-focused investigators with support from three IDDRC Cores (Genetics, Brain Imaging, and Animal Behavior). At the completion of this project, we will understand the effects of C-terminal truncating MN1 variants on gene regulation and brain development. Our specific aims are: 1. To dissect the role of MN1 in transcriptional regulation using stem cell derived models; 2. To dissect the developmental mechanisms underlying MN1- related PMG and RES in mice.

项目概要-研究项目 智力和发育障碍（IDDs）的潜在机制主要仍然是 未知相当多的IDDs患者的大脑发育 与相当高的发病率和死亡率相关的畸形。这项建议 重点关注一种新发现的IDD病症（MCTT综合征），其特征为IDD，癫痫， 特征性颅面差异和两种重要的脑畸形：多小脑回畸形 (PMG)和菱脑突触（RES）。PMG是许多IDD的共同特征， 与发育障碍和癫痫密切相关。虽然PMG被认为是 由于异常的神经元迁移，其原因和分子机制仍不完全 但很少有好的动物模型。RES是一种独特的小脑畸形 以小脑半球的融合为特征，部分或完全没有小脑半球。 可识别的小脑蚓部;几乎不知道的原因和机制 潜在的RES，并且不存在动物模型。该项目代表了协同合作 在三个IDDRC核心的支持下， （遗传学，脑成像和动物行为）。在这个项目完成后，我们将 了解C末端截短MN1变体对基因调控和大脑的影响 发展我们的具体目标是：1.分析MN1在转录调控中的作用 使用干细胞衍生的模型; 2.为了剖析MN1的发育机制， 相关PMG和RES。