MRC DiMeN Doctoral Training Partnership: Functional Characterization of a Truncation Mutation Associated with Intellectual Disability

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. 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, we discovered a truncation mutation in a gene which co-segregates in the homozygous state with ID. This unpublished finding is novel because the affected gene has not been associated with ID before.

This PhD project aims to increase understanding of the effects of loss of the ID-associated gene on phenotypes relevant to cognition and ID, and also to explore the cell biological mechanisms underlying the condition. We already know that knockdown of the Drosophila orthologue leads to a deficit in long-term memory in fruit flies, and we have preliminary data showing that knock-out (KO) mice that lack the murine orthologue of the ID-associated gene exhibit reduced novel object recognition memory. You will employ a wide range of cutting-edge behavioural, molecular biology, imaging and neurophysiology techniques to further characterize the KO mice. Questions that you will address include the extent of the cognitive impairment in the KO mice; the density and morphology of various neural cell types; mitochondrial function and calcium homeostasis. Your studies will provide information on the role of the ID-associated gene in cognition, and how homozygous mutation of the gene leads to ID. Ultimately, this knowledge will aid the development of better treatments for ID caused by mutation of the gene.

Benefits of being in the DiMeN DTP:
This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.
We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.
Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards
Further information on the programme can be found on our website:
http://www.dimen.org.uk/