ACC: Callosal Agenesis as a Window into Common Neurodevelopmental Disorders

ACC：胼胝体发育不全是了解常见神经发育障碍的窗口

基本信息

批准号：
10157738
负责人：
Elliott Sherr
金额：
$ 68.16万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-03-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10157738
关键词：
AMPA Receptors Affect Aicardi&apos s syndrome Animal Model Architecture Binding Biological Models Biology Biotinylation Brain Brain imaging CREB1 gene Candidate Disease Gene Caring Cell model Cerebral Palsy Cerebral hemisphere Cerebrum Clinical Clinical Data Code Cognition Disorders Collaborations Communities Complex Corpus Callosum Data Development Disease Enrollment Ensure Epilepsy Family Fiber Foundations Genes Genetic Genetic Predisposition to Disease Genetic Variation Genetic study Genome Genomic Segment Genomics Glutamates Goals Grant Hand Human Incidence Inherited Intellectual functioning disability International Laboratories Link Modeling Mus Mutation NFIB gene Neurodevelopmental Disorder Neurology Neurons Parents Participant Patients Phenotype Play Population Positioning Attribute Probability Proteins Public Health Regulation Research Role Schizophrenia Signal Pathway Structure Synaptic Transmission Synaptic plasticity Syndrome Testing Tissues Validation Variant Work autism spectrum disorder base brain malformation brain tissue clinical phenotype cohort de novo mutation exome exome sequencing fetal gene discovery genetic information genome-wide imaging study improved insertion/deletion mutation nanopore neuronal excitability novel outreach postnatal rare condition receptor receptor recycling recruit transcription factor treatment strategy

项目摘要

Abstract: The corpus callosum – the largest fiber tract in the human brain, connects and integrates the two cerebral hemispheres. Agenesis of the corpus callosum (ACC) with an incidence of 1 in 2,000 occurs in rare syndromes and in common neurodevelopmental disorders (NDD) including epilepsy, intellectual disability (ID), autism spectrum disorder (ASD), cerebral palsy and schizophrenia. Collectively these affect more than 5% of the population and constitute a major public health concern. Recent evidence including from our team, points to the importance of genetic etiologies. Our whole exome efforts in this grant’s initial submission identified 70 ACC genes that reached genome-wide significance, of which many of which are strong novel candidate genes that need further validation. Based on population estimates, we expect that several hundred additional genes will cause ACC. To discover the full range of ACC genetics and to make progress using model systems, we bring together an outstanding investigative team that has made significant contributions to the biology of ACC. Together we will advance gene discovery, and tackle key questions on CC development. To do so we will: Aim 1: Identify novel de novo genetic causes of ACC and NDD. To do so, we will recruit, obtain clinical data and conduct WES for 1000+ ACC trios from UCSF and collaborators. We will also receive genetic information from 2000+ trios from the two largest commercial exome sequencing laboratories in the US, GeneDx and Invitae. We will also leverage the community’s gene discovery efforts using MatchMaker, and work with the IRC5 (international research consortium for the corpus callosum and cerebral connectivity: www.IRC5.org), which the PI’s co-founded. These combined efforts will ensure robust novel gene discovery. Aim #2: Discover genetic causes of ACC beyond germline de novo coding variants. In addition to gene discovery above, we hypothesize that many ACC cases are caused by mutations in complex genomic regions. We will initially focus on Aicardi syndrome, a highly complex yet distinctive brain malformation disorder. We will conduct short-read deep WGS from affected brain tissue (6 in hand) and other tissues, collaborating with the Broad Mendelian Genome Center, to perform long-read sequencing to resolve complex genomic architecture and other difficult to sequence regions. We will also utilize the same work flow to tackle gene discovery in similarly phenotypically unified conditions in particular focusing on multiplex cases. Aim #3: Engage in functional confirmation and analysis of ACC candidate genes. During our current cycle, we have made significant progress studying the biology C12ORF57. In this proposal, we will advance this directly, by 1. Studying the protein interaction network for C12ORF57 and CAMKIV. We will also study the signaling pathways that link CAMKIV to the transcription factor CREB and to regulation of AMPA receptors, the key glutamatergic receptors for excitatory neural transmission. This work may have critical implications for treatment strategies in epilepsy and possibly disorders of cognition.

摘要：call体 - 人脑中最大的纤维道，连接并整合了两者大脑半球。综合征和常见的神经发育障碍（NDD），包括癫痫，智障（ID），自闭症谱系障碍（ASD），脑瘫和学历。人口构成了主要的公共卫生问题。遗传病因的重要性。达到全基因组显着性的ACC基因，其中是Orere强的strondididel candidide基因这需要进一步的验证，我们预计会切断其他基因会导致ACC发现全部ACC遗传学并使用模型系统取得进展将一个外出的调查团队汇集为ACC的生物学做出了重大贡献。我们将共同提高基因发现，并解决有关CC开发的关键问题。目标1：确定新颖的遗传原因ACC和NDD，我们将招募，获得临床数据并从UCSF和合作者进行1000多个ACC的WES。来自美国两个最大的商业外部测序实验室的2000+三重奏的信息， Genedx和Invitae。与IRC5（Collosum and Cerebral Connection国际研究联盟）合作 www.irc5.org），Pi的共同创建将确保强大的新型基因发现。目的2：除了基因之外，还要发现ACC超出生殖线的遗传原因。在上面的发现，我们假设许多ACCCCase是由复杂基因组区域突变引起的。我们将重点介绍Aicardi综合征，这是一种高度复杂而独特的大脑畸形障碍与受影响的脑组织（6个）和其他组织进行简短阅读的深WG，与您合作宽阔的门德尔基因组中心，进行长阅读测序以解决xplex基因组结构和其他序列区域的difficalt。类似地表型统一的核心案例。目标＃3：在我们当前的ACC候选基因的功能确认和分析循环，我们在此提案中研究了生物学C12orf57。直接研究C12orf57和Camkiv的蛋白质相互作用网络。将CAMKIV与转录因子CREB和AMPA受体的调节联系起来的信号通路，兴奋性神经传播的关键谷氨酸受体可能对癫痫病和可能的认知疾病的治疗策略。