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：
10661707
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/10661707
关键词：
Alleles Animal Behavior Animal Model Antisense Oligonucleotides Behavioral Assay Brain Brain imaging C-terminal Candidate Disease Gene 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 Heterozygote High Prevalence Histology Human Individual Intellectual and Developmental Disabilities Research Centers Intellectual functioning disability Investigation Magnetic Resonance Imaging Methods Microgyria Modeling Molecular Morbidity - disease rate Mus Neuronal Differentiation 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 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 - 研究项目智力和发展障碍（IDD）的基础机制在很大程度上仍然是未知。大量具有IDD的人有发育性的大脑与考虑发病率和死亡率相关的畸形。这个建议专注于新确定的IDD条件（MCTT综合征），其特征是IDD，癫痫，特征性的颅面差异和两个重要的大脑畸形：多毛虫病（PMG）和菱形脑酶（RES）。 PMG是许多IDD中的常见功能，是与发育障碍和癫痫密切相关。虽然已知PMG是由于神经元的异常迁移，原因和分子机制仍然不完全理解，很少有好动物模型。 RES是一个独特的小脑畸形以部分或完全没有A的融合为特征的小脑半球可以识别的小脑vermis;关于原因和机制几乎一无所知基础Res，没有动物模型。该项目代表了协同的合作在三个IDDRC核心的支持下，人类和小鼠模型的研究人员之间（遗传学，脑成像和动物行为）。该项目完成时，我们将了解C末端截断MN1变体对基因调节和脑的影响发展。我们的具体目的是：1。剖析MN1在转录调节中的作用使用干细胞得出的模型； 2。剖析MN1-的发展机制相关的PMG和RES在小鼠中。