University of Dundee

4 Year MRC PhD Programme: Investigation of an E3 Ubiquitin Ligase Mutated in Intellectual Disability

Intellectual disability is a genetically heterogeneous and poorly understood developmental disorder estimated to affect 1-2% of the world’s population. The X-chromosome is a critical centre for genes involved in intellectual development, and X-Linked Intellectual Disability (XLID) forms an important class of intellectual disability. Despite the large number of genetic studies in this area, the molecular mechanisms underpinning intellectual disability remain unknown. Recently, mutations in the X-linked RNF12/RLIM E3 ubiquitin ligase were identified as drivers of XLID. Excitingly, our lab has demonstrated that multiple RNF12 XLID mutations in the catalytic domain and substrate-binding region disrupt RNF12 E3 ubiquitin ligase activity, suggesting that deregulated protein ubiquitylation represents an underlying molecular basis of intellectual disability.

This project aims to pinpoint mechanisms of RNF12 regulation and function to better understand the molecular underpinnings of intellectual disability. A key focus will be to investigate regulation of RNF12 E3 ligase activity by protein kinase signaling. The candidate will also employ cutting-edge mass-spectrometry approaches to identify and characterize novel RNF12 substrates. Further, the project aims to establish the overarching molecular functions of RNF12 by identifying transcriptomic and proteomic signatures using RNA-SEQ and proteomic profiling technologies. These investigations will uncover new regulatory targets that may be relevant in XLID disease etiology.

 These molecular investigations could dove-tail with efforts to develop an animal model of RNF12-driven XLID. Excitingly, we are currently developing RNF12 XLID mice, which will be phenotyped for adaptive and cognitive abnormalities associated with intellectual disability. These include impaired social behavior, aggression and defective memory, and locomotive and motor dysfunction. This model will be examined for pathological features of XLID, including impaired dendritic arborisation and spine formation, and abnormal development, specification and morphology of distinct cerebral cell populations. Finally, we aim to investigate ubiquitylation of novel RNF12 substrates in the developing nervous system of RNF12 XLID mice. This collaborative project will provide insights into the role of protein ubiquitylation in intellectual development, and identify mechanisms by which defects in this system may lead to intellectual disability.

 

References: 1) Bustos et al submitted (2017).

2) Fernandez-Alonso et al EMBO Reports 18, 1108-22 (2017).

3) Williams et al Cell Reports 16, 1820-8 (2016).

 

Eligibility