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

基本信息

批准号：
10224297
负责人：
DANIEL DOHERTY
金额：
$ 25.08万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
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/10224297
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 cell model stem cells transcription factor transcriptome sequencing

项目摘要

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.

项目摘要 - 研究项目智力和发育障碍（IDD）的潜在机制在很大程度上仍然存在尚不清楚，相当数量的 IDD 患者的大脑处于发育状态。与相当大的发病率和死亡率相关的畸形。重点关注一种新发现的 IDD 病症（MCTT 综合征），其特征是 IDD、癫痫、特征性颅面差异，以及两种重要的脑部畸形：多小脑回 (PMG) 和菱形脑突 (RES) 是许多 IDD 的共同特征。尽管已知 PMG 与发育障碍和癫痫密切相关。由于神经迁移异常，其原因和分子机制尚不完全 RES 是一种独特的小脑畸形，目前尚无良好的动物模型。其特征是小脑半球融合，部分或完全缺失公认的小脑蚓部的原因和机制几乎一无所知； RES 基础，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，以人类和小鼠模型为重点的研究人员之间进行合作（遗传学、脑成像和动物行为）。了解 C 端截短的 MN1 变体对基因调控和大脑的影响我们的具体目标是： 1. 剖析 MN1 在转录调控中的作用。使用干细胞衍生模型；2. 剖析 MN1- 的发育机制小鼠中相关的 PMG 和 RES。