Research area: Clinical Sciences > Neurodisability and Rehabilitation

Overview

Intellectual disability occurs in two to three per cent of newborns, for a variety of reasons, including environmental factors, chromosomal abnormalities, and variations in single genes. Recently, it has been recognised that intellectual disability resulting from inborn errors in the chromatin machinery may be treatable. Over 70 genetic syndromes have so far been identified in this category. 

Our goals 

This project focuses on variations in chromatin factors and chromatin-modifying enzymes found in patients with intellectual disability because chromatin changes are reversible, and these classes of molecules are well-established as therapeutic targets in other disorders.

Exploring treatments of genetic forms of intellectual disability

Histones wrap and compact DNA into 'chromatin'. Specialised proteins can modify histones to control which genes are 'switched on' (expressed) or 'switched off' (silenced). If this process is dysregulated, severe neurodevelopmental outcomes result.

This laboratory-based study is investigating several chromatin disorders to better understand how dysregulation of histone modifications impacts the molecular and cellular events critical for neurodevelopment and brain function.

This project is also exploring exciting new treatments capable of modulating the chromatin landscape and improving neurodevelopmental processes. The long-term aim is to bring these therapies to patients in clinical trials.

Towards treatment for genetic syndromes in the KAT6 genes

We are focusing on KAT6 syndromes as an example of a disorder caused by dysregulated histone modification. KAT6 genes normally produce histone acetyltransferases – proteins that modify histones by applying acetyl- groups at specific histone sites and influencing chromatin structure which therefore controls the expression of other genes.

Changes in KAT6 genes lead to a range of neurodevelopmental challenges including intellectual disability, speech and language disorders and a diagnosis of an autism. Since the acetylation of histones by KAT6A can be modified, these conditions may be treatable. In this project, we are investigating whether cell models of the brain hold clues about why children with these conditions develop intellectual disability.

The work also aims to identify a biomarker that can be used in a clinical trial that investigates supplementing the precursor metabolites in children with KAT6 disorders.

Our research team

This work is a collaboration with the Neurogenetics group within the Bruce Lefroy Centre.

Research leads

• Professor David Amor
• Professor Paul Lockhart

Team members

• Senior Researcher Dr Jordan Wright
• PhD students Inbal Kantor and Dr Sarah Donoghue
  
  

Publications

Wright JL, Jiang Y, Nayar SG, Li H, Richardson WD. The INO80 Chromatin Remodeling Complex Regulates Histone H2A.Z Mobility and the G1-S Transition in Oligodendrocyte Precursors. Glia Epub 2025.

Donoghue S, Wright J, Voss AK, Lockhart PJ, Amor DJ. The Mendelian disorders of chromatin machinery: Harnessing metabolic pathways and therapies for treatment. Mol Genet Metab 142(1): 108360 2024.

Donoghue SE, Amor DJ. Intellectual disability: A potentially treatable condition. J Paediatr Child Health. 2024 Jul;60(7):273-278.

Contact us

These studies are recruiting by referral only. If you are interested in learning more, please contact Professor David Amor, Group Leader, Neurodisability and Rehabilitation.

Email: show email address