ACC: Callosal Agenesis as a Window into Common Neurodevelopmental Disorders

摘要：人类大脑中最大的纤维束--胼胝体连接并整合了这两者。 大脑半球。罕见的发生于2,000人中就有1人的骨痂发育不全 综合征和常见的神经发育障碍(NDD)，包括癫痫、智力残疾(ID)、 自闭症谱系障碍(ASD)、脑瘫和精神分裂症。这些因素总共影响了超过5%的 并构成了一个重大的公共卫生问题。最近的证据，包括我们团队的，积分 遗传病因学的重要性。我们在最初提交的这笔赠款中所做的全部工作确定了70 达到全基因组意义的ACC基因，其中许多是强有力的新候选基因 这需要进一步的验证。根据种群估计，我们预计会有数百个额外的基因 会导致ACC。为了发现全范围的ACC遗传学并利用模型系统取得进展，我们 汇聚一支对ACC生物学做出重大贡献的杰出调查团队。 我们将共同推进基因发现，解决CC发展的关键问题。为此，我们将： 目的1：确定ACC和NDD的新的新的遗传原因。为了做到这一点，我们将招募、获得临床 来自加州大学旧金山分校和合作者的1000+ACC三人组的数据和执行WES。我们还将收到基因 来自美国两个最大的商业外显子组测序实验室的2000多个三人组的信息， GeneDx和Invitae。我们还将使用MatchMaker利用社区的基因发现努力，以及 与IRC5(国际研究联盟)合作，研究胼胝体和大脑连通性： (www.IRC5.org)，这是PI的联合创始人。这些联合努力将确保强有力的新基因发现。 目的#2：发现生殖系新生编码变异以外的ACC的遗传原因。除了基因 根据上面的发现，我们假设许多ACC病例是由复杂基因组区域的突变引起的。 我们首先将重点放在艾卡迪综合征上，这是一种高度复杂但独特的大脑畸形疾病。我们会 从受影响的脑组织(手头有6个)和其他组织进行短读深度WGS，与 广泛的孟德尔基因组中心，执行长阅读测序，以解决复杂的基因组结构 以及其他难以测序的区域。我们还将利用相同的工作流程来处理基因发现 同样，表观上统一的条件，特别侧重于多重情况。 目的#3：对ACC候选基因进行功能验证和分析。在我们目前的 周期，我们对生物学C12ORF57的研究取得了重大进展。在这项提案中，我们将推进 研究了C12ORF57与CAMKIV的蛋白质相互作用网络。我们亦会研究 将CAMKIV连接到转录因子CREB和AMPA受体调节的信号通路， 兴奋性神经传递的关键谷氨酸能受体。这项工作可能会对 癫痫和可能的认知障碍的治疗策略。

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.