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

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.

Intellectual disability (ID) is a common neurodevelopmental disorder with an onset of cognitive impairment before the age of 18 years and is characterized by significant limitations in intellectual functioning and adaptive behaviour. ID can have a devastating effect on the lives of the affected individuals and their families and is a major challenge at the clinical level. The condition affects 1-3% of the world population; however, its prevalence in the developing world is almost twice that of the affluent world. Among the known causes, ~50% of ID cases have a genetic aetiology, such as chromosomal abnormalities or mutations in specific genes. Consanguineous marriages are practiced by about 20% of the human population and lead to a marked increase in the frequency of severe recessive disorders. Homozygosity mapping has been proven to be an effective method for gene identification in consanguineous populations. To this end, we recruited six families derived from first-cousin marriages in which at least two children were affected by ID. In one family, genetic testing revealed a truncation mutation in PDZD8 that co-segregates in the homozygous state with ID. Our overarching aim now is to elucidate the role of PDZD8 in cognition, and how homozygous disruption of PDZD8 leads to ID. We recently discovered that knockdown of the PDZD8 orthologue in Drosophila (CG10362) led to a deficit in long-term memory. The availability of Pdzd8 null mice provides direct access to the biological effects of PDZD8 deficiency in mammals. Therefore, we propose to use the Pdzd8tm1b mouse model to increase understanding of the effects of disruption of PDZD8 expression on phenotypes relevant to cognition and ID. If we find that Pdzd8 null mice exhibit a phenotypic resemblance to ID, we will prepare a subsequent proposal to employ these mice as a model system for testing hypotheses about the mechanisms underlying the condition, and translational evaluation of treatments for the condition.