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

• 批准号: 10789478
• 负责人: Elliott Sherr
• 金额: $ 6.14万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 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/10789478
• 关键词: AMPA Receptors; Affect; Aicardi' s syndrome; Animal Model; Architecture; Biological Models; Biology; Brain; CREB1 gene; Candidate Disease Gene; Cell model; Cerebral Palsy; Cerebral hemisphere; Cerebrum; Clinical Data; Code; Cognition Disorders; Collaborations; Communities; Complex; Corpus Callosum; Development; Disease; Ensure; Epilepsy; Fiber; Genes; Genetic; Genetic Predisposition to Disease; Genetic study; Genome; Genomic Segment; Genomics; Glutamates; Grant; Hand; Human; Incidence; Intellectual functioning disability; International; Laboratories; Link; Mutation; Neurodevelopmental Disorder; Participant; Phenotype; Population; Positioning Attribute; Proteins; Public Health; Regulation; Research; Schizophrenia; Signal Pathway; Synaptic Transmission; Tissues; Validation; Variant; Work; autism spectrum disorder; brain malformation; brain tissue; exome; exome sequencing; gene discovery; genetic information; genome-wide; novel; rare condition; receptor; recruit; transcription factor; treatment strategy

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 脑半球。 callosum callosum（ACC）的发育不全发生在2,000中，罕见发生 综合征和常见的神经发育障碍（NDD），包括癫痫，肠道残疾（ID），， 自闭症谱系障碍（ASD），脑瘫和精神分裂症。这些总共影响了超过5％ 人口并构成了一个主要的公共卫生问题。最近的证据，包括我们团队的积分 对于遗传病因的重要性。我们在这笔赠款初始提交中确定的全部外部努力已经确定了70 达到全基因组意义的ACC基因，其中许多是强大的新型候选基因 需要进一步验证。根据人口的估计，我们预计还有数百个基因 会导致ACC。为了发现各种ACC遗传学并使用模型系统取得进展，我们 将一个杰出的调查团队汇集在一起​​，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。为此，我们将： 目标1：确定新颖的从头遗传原因和NDD。为此，我们将招募，获得临床 来自UCSF和合作者的1000+ ACC三重奏的数据并进行WES。我们还将收到通用 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。我们还将利用社区的基因发现工作，使用媒人， 与IRC5（国际call体和脑连通性的国际研究联盟： www.irc5.org），Pi的共同创建。这些合并的努力将确保强大的新颖基因发现。 AIM＃2：发现ACC超越新编码变体的遗传原因。除了基因 在上面的发现，我们假设许多ACC病例是由复杂基因组区域突变引起的。 我们最初将专注于Aicardi综合征，这是一种高度复杂而独特的脑畸形障碍。我们将 从受影响的脑组织（手工6）和其他时机进行简短阅读的深WG，与 广泛的门德尔基因组中心，进行长阅读测序以解决复杂的基因组结构 以及其他难以序列区域。我们还将利用相同的工作流来解决基因发现 类似地，表面上的统一条件特别关注多种情况。 目标＃3：参与ACC候选基因的功能确认和分析。在我们当前 循环，我们在研究生物学C12ORF57方面取得了重大进展。在此提案中，我们将进步 直接通过1。研究C12ORF57和CAMKIV的蛋白质相互作用网络。我们还将研究 将CAMKIV与转录因子CREB和AMPA接收器的调节的信号通路， 用于兴奋性神经传播的关键谷氨酸能受体。这项工作可能对 癫痫病和可能的认知疾病的治疗策略。

项目成果

Ultra-high-field MR imaging in polymicrogyria and epilepsy.

• DOI: 10.3174/ajnr.a4116
• 发表时间: 2015-03
• 期刊: AJNR. American journal of neuroradiology
• 作者: De Ciantis A;Barkovich AJ;Cosottini M;Barba C;Montanaro D;Costagli M;Tosetti M;Biagi L;Dobyns WB;Guerrini R
• 通讯作者: Guerrini R

Analysis of 17 genes detects mutations in 81% of 811 patients with lissencephaly.

• DOI: 10.1038/gim.2018.8
• 发表时间: 2018-11
• 期刊: Genetics in medicine : official journal of the American College of Medical Genetics
• 作者: Di Donato N;Timms AE;Aldinger KA;Mirzaa GM;Bennett JT;Collins S;Olds C;Mei D;Chiari S;Carvill G;Myers CT;Rivière JB;Zaki MS;University of Washington Center for Mendelian Genomics;Gleeson JG;Rump A;Conti V;Parrini E;Ross ME;Ledbetter DH;Guerrini R;Dobyns WB
• 通讯作者: Dobyns WB

Heterozygous variants in MYH10 associated with neurodevelopmental disorders and congenital anomalies with evidence for primary cilia-dependent defects in Hedgehog signaling.

• DOI: 10.1016/j.gim.2022.07.005
• 发表时间: 2022-08
• 期刊: Genetics in medicine : official journal of the American College of Medical Genetics
• 作者: Alexander M. Holtz;Rachel Vancoil;Elizabeth A VanSickle;D. A. Carere;Kara A. Withrow;E. Torti;J. Juusola-J.

A developmental and genetic classification for malformations of cortical development: update 2012.

• DOI: 10.1093/brain/aws019
• 发表时间: 2012-05
• 期刊: Brain : a journal of neurology
• 作者: Barkovich AJ;Guerrini R;Kuzniecky RI;Jackson GD;Dobyns WB
• 通讯作者: Dobyns WB

Infantile Spasms of Unknown Cause: Predictors of Outcome and Genotype-Phenotype Correlation.

• DOI: 10.1016/j.pediatrneurol.2018.04.012
• 发表时间: 2018-10
• 期刊: Pediatric neurology
• 影响因子: 3.8
• 作者: Yuskaitis CJ;Ruzhnikov MRZ;Howell KB;Allen IE;Kapur K;Dlugos DJ;Scheffer IE;Poduri A;Sherr EH
• 通讯作者: Sherr EH