Understanding how mutations in the kinase TLK2 cause a neurodevelopmental disorder

Tousled-like kinase 2 (TLK2) was recently identified as a novel genetic locus for a neurodevelopmental disorder. Patients predominantly possess de novo mutations in TLK2, leading to a reduction in its expression or kinase activity. TLK2 syndrome (named Mental Retardation Autosomal Dominant 57; MRD57) is characterised by a range of nervous system abnormalities, including intellectual disability, psychomotor developmental delay, epilepsy, autism and behavioural issues, in addition to abnormalities in the head and neck, musculoskeletal system and other developmental issues. TLK2 has been implicated in genome stability, regulating chromatin assembly in S-phase, DNA repair and transcription, however, the role of TLK2 in the nervous system is poorly understood. This project will draw on expertise in neuronal kinase signalling in the Evans and Hahn labs to shed light on how human TLK2 mutations affect neuronal development in MRD57. The project will employ a wide range of proteomic, molecular cell biology and protein biochemistry approaches to identify the neuronal substrates of TLK2 and determine how they are regulated by phosphorylation. The role of TLK2 signalling in healthy neuronal development will then be established using cell models of neuronal differentiation. Finally, the project will discover how these pathways are affected by the loss of TLK2, with the aim of better understanding the molecular pathology of MRD57.

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