IMPC: Disruption of PDZD8 as a potential cause of intellectual disability

IMPC：PDZD8 的破坏是智力障碍的潜在原因

• 批准号: MR/R014736/1
• 负责人: Steven Clapcote
• 金额: $ 4.34万
• 依托单位: University of Leeds
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR014736%2F1
• 关键词: IMPC; Disruption; PDZD8; potential; cause

Intellectual disability, also known as mental retardation, is a life-long condition that impairs affected individuals' memory, problem solving, language and visual comprehension as well as daily living skills such as self-care, independence and interpersonal communication. The condition is poorly treated, in part because we know little about the root causes in most cases. However, we do know that intellectual disability can be inherited, suggesting that defective genes might be involved. This project will look at one particular gene, PDZD8, which we recently discovered to be damaged in some people with intellectual disability. Working out how the faulty PDZD8 gene might cause intellectual disability in people is constrained by ethical limitations on the studies that we can undertake on human subjects. But it turns out that a strain of laboratory mouse also has a faulty PDZD8 gene that mimics the gene defect in some ID patients. So we will use these PDZD8 mutant mice to try to learn more about the role of PDZD8 in intellectual disability, which might give us clues to better treatments in the future.Behavioural tests are the most appropriate for investigating the link between the faulty PDZD8 gene and intellectual disability because abnormal behaviours are the primary symptoms of the condition. Although mice do not fully replicate human behaviours, specially-designed tests can detect behavioural abnormalities in mice that resemble human symptoms. We will use this approach to identify the behavioural effects of the faulty PDZD8 gene in mice. We will also examine the mice for abnormalities in the size and shape of their brains.At the end of this 1-year project, we expect to have determined whether the faulty PDZD8 gene causes intellectual disability-related changes in the mice. If PDZD8 mutant mice do exhibit abnormalities resembling symptoms of intellectual disability, they will be used in future studies to further investigate how the faulty PDZD8 gene affects brain function, and to test new treatments for the condition.

智力残疾，也被称为智力迟钝，是一种终身疾病，损害了受影响个人的记忆、解决问题的能力、语言和视觉理解能力，以及自理、独立和人际交往等日常生活技能。这种情况没有得到很好的治疗，部分原因是我们对大多数情况下的根本原因知之甚少。然而，我们确实知道智力残疾是可以遗传的，这表明可能与有缺陷的基因有关。这个项目将着眼于一个特殊的基因，PDZD8，我们最近发现它在一些智力残疾的人身上被破坏了。研究有缺陷的PDZD8基因是如何导致人类智力残疾的，受到了人类研究的伦理限制。但事实证明，一种实验室小鼠也有缺陷的PDZD8基因，这种基因模仿了一些ID患者的基因缺陷。因此，我们将利用这些PDZD8突变小鼠，试图更多地了解PDZD8在智力残疾中的作用，这可能为我们未来更好的治疗提供线索。行为测试是调查PDZD8基因缺陷与智力残疾之间联系的最合适的方法，因为异常行为是这种疾病的主要症状。虽然小鼠不能完全复制人类的行为，但专门设计的测试可以检测出与人类症状相似的小鼠的行为异常。我们将使用这种方法来确定错误的PDZD8基因对小鼠的行为影响。我们还将检查小鼠大脑的大小和形状是否异常。在这个为期一年的项目结束时，我们希望能够确定PDZD8基因缺陷是否会导致小鼠智力残疾相关的变化。如果PDZD8突变小鼠确实表现出类似智力残疾症状的异常，它们将在未来的研究中进一步研究PDZD8基因缺陷如何影响大脑功能，并测试治疗这种疾病的新方法。

项目成果

PDZD8 Disruption Causes Cognitive Impairment in Humans, Mice, and Fruit Flies.

• DOI: 10.1016/j.biopsych.2021.12.017
• 发表时间: 2022-08-15
• 期刊: Biological psychiatry
• 影响因子: 10.6