Mechanism of AUTS2-linked neurodevelopmental disorders

项目总结/摘要 许多类型的神经精神疾病具有显著的遗传成分，尽管它们通常是 被认为涉及相互作用的基因的混合。然而，一些疾病也可能是由罕见的基因突变驱动的。 单个基因位点，突出了在神经发育中具有基础和关键作用的基因。一个这样的基因座，AUTS 2， 最初是在一对自闭症双胞胎中被发现的。然而，AUTS 2突变已经被 与广泛的神经系统疾病有关，包括癫痫、精神分裂症、双相情感障碍、成瘾性 举几个例子。因此，这一单一的基因区域涉及异常广泛的遗传学。 具有深远社会影响的神经精神疾病。然而，AUTS 2区突变 对这些疾病的易感性尚不清楚。使遗传图复杂化的是，大多数人类AUTS 2 突变是基因组重排，可能影响其他相邻基因的功能。特别 在这方面感兴趣的是WBSCR 17，其在保守的地形相关结构域中与AUTS 2连接 (TAD)提示基因的协同调节。虽然Auts 2小鼠“敲除”突变表达了某些 表型可以被认为是平行于某些神经精神特征，他们没有提供一个 AUTS 2相关疾病的引人注目的模型。该项目的重点是一种新的小鼠突变，称为16 Gso， 这会破坏Wb 17-Auts 2基因并使这两个基因失调。尽管有这种复杂的遗传效应，16 Gso 突变体表现出形态、行为和大脑结构异常，模拟了人类AUTS 2 表型非常好。我们假设Wb 17有助于16 G50和AUTS 2相关的人类细胞凋亡。 通过与Auts 2在延长，存活， 以及发育中和成年大脑中神经元过程的连通性。此外，我们建议，扰动 这一途径的缺陷使受影响的个体易患各种神经精神疾病。这项建议 通过定义Wb 17至16 G50表型的贡献，专注于解决这些假设， Wb 17和Auts 2之间的遗传相互作用。我们将研究细胞功能的调节， 在细胞模型中的两个位点，并定义控制这些连锁基因的调节机制。一起 这些数据将为基因型：表型相关性提供新的解释， 人类神经系统疾病的易感性。

PROJECT SUMMARY / ABSTRACT Many types of neuropsychiatric conditions have a significant genetic component, although they are generally thought to involve a mix of interacting genes. However, some disorders can also be driven by rare mutations in single genetic loci, highlighting genes with basic and pivotal roles in neurodevelopment. One such locus, AUTS2, was originally discovered as disrupted in a pair of autistic twins. However, AUTS2 mutations have since been linked to a wide range of neurological disorders, including epilepsy, schizophrenia, bipolar disorder, addictive behaviors to name a few. This single genetic region is thus implicated in an exceptionally broad range of neuropsychiatric disorders with profound societal impact. However, the way that AUTS2-region mutations predispose to these diseases is not well understood. Complicating the genetic picture, most human AUTS2 mutations are genomic rearrangements that could impact the functions of other neighboring genes. Of particular interest in this regard is WBSCR17, which is linked to AUTS2 in a conserved topographically associating domain (TAD), suggesting co-regulation of the genes. While Auts2 mouse “knockout” mutations express certain phenotypes that could be considered parallel to certain neuropsychiatric traits, they have not provided a compelling model for AUTS2-linked disease. This project is focused on a novel mouse mutation, called 16Gso, which disrupts the Wbscr17-Auts2 TAD and dysregulates both genes. Despite this complex genetic effect, 16Gso mutants display morphological, behavioral, and brain structural abnormalities that model human AUTS2 phenotypes strikingly well. We hypothesize that Wbscr17 contributes to 16Gso and AUTS2-linke human neurological phenotypes by interacting with Auts2 in a basic cellular pathway required for the extension, survival, and connectivity of neuronal processes in the developing and adult brain. Further we propose that disturbance of this pathway leaves affected individuals susceptible to a wide range neuropsychiatric disease. This proposal is focused on addressing these hypotheses by defining the contributions of Wbscr17 to 16Gso phenotypes, and the genetic interactions between Wbscr17 and Auts2. We will investigate the cellular functions regulated by the two loci in a cellular model, and define the regulatory mechanisms that control these linked genes. Together these data will provide novel explanations for genotype:phenotype correlations in a genetic region linked broadly to susceptibilities to human neurological disease.