Neurogenetic Research (BLC)
Gene discovery and functional characterisation of proteins contributing to neurodevelopmental and neurogenetic disorders including autism, brain malformations and ataxia.
Our group was established in 2004 to develop laboratory-based molecular neuroscience research within the Murdoch Children's Research Institute and enhance the established clinical and public health research activities of the Bruce Lefroy Centre (BLC).
Our team uses powerful modern genomic technologies, including high-density SNP arrays and Next Generation short-read and long-read sequencing to identify changes in genes that cause neurogenetic and neurodevelopmental conditions. The characterisation of the disease-causing genes involves analysing cells and animal models to understand the molecular mechanism underlying the condition. Identification of disease-causing genes is beneficial to both the affected individual and their family.
A genetic diagnosis helps improve clinical outcomes and genetic counselling provides the potential for pre-implantation genetic diagnosis and potentially targeted treatments or therapeutics. The group’s studies aim to understand the mechanisms underlying disease and are an essential prerequisite for the development of treatment programs and prevention or onset-delay strategies for brain and mind disorders.
Our projects
Using monogenic conditions to understand the neurobiology of autism
In a subset of individuals with autism (15-20%), the condition is part of a clinically defined syndrome resulting from a single gene disorder. Therefore, studying these conditions provides a pathway to systematically explore the neurobiological mechanisms of autism. Neurofibromatosis type 1 (NF1) is one example and is an autosomal dominant disorder caused by a loss-of-function mutation in the NF1 gene.
In this project, we investigate developmental pathways to autism by combining the power of accurate clinical phenotyping with state-of-the-art laboratory protocols including neuronal modelling using patient derived stem cells. These laboratory-based assays enable us to determine how well brain cells grow, develop and communicate with one another and the pathways that may be dysregulated in autism. This unique research strategy will provide major insights into the molecular mechanisms of autism in NF1 specifically, with implications for meaningful biomarker discovery, therapy and ultimately treatment of autism more broadly.
Discovery of new treatments for brain development disorders linked to epigenetic regulatory genes
Humans have a highly expanded cortex compared to other mammals which is responsible for our unique intellectual capacity. Cortical development during embryogenesis requires tight control over gene expression to ensure cells proliferate, differentiate and mature in a precise and timely manner. Gene expression is broadly controlled by epigenetic markers on chromatin and DNA surrounding genes, therefore it is not surprising that mutations found in epigenetic regulators are often linked with disorders where cortical malformation and intellectual disability is observed.
Using a multi-systems approach we aim to determine how mutations in chromatin regulator genes identified in individuals with ID effect cortical development utilising both patient-derived iPS cells and mouse models. As epigenetic marks are reversible, we postulate that stimulation of opposing epigenetic pathways may partially rectify the unbalanced epigenetic landscape. We therefore aim to identify compounds that modulate histone methylation and acetylation pathways to restore proper gene regulation during cortical development.
Understanding Disease Mechanism and Improving Clinical Management of Children with Epilepsy
Epilepsy is a disorder of the brain that affects over 20 million children worldwide and is one of the medicine’s oldest recognized conditions. Children with epilepsy have recurrent seizures which can take many forms including staring spells, muscle jerking and loss of consciousness or unusual feelings. Early intervention is essential to reduce seizure burden and prevent adverse developmental consequences. Medications are tried first, however in up to one third of children these fail to provide seizure control, and are often associated with side effects.
One of the most common causes of drug resistant epilepsy in children is a lesion of the brain that results from abnormal development during the pregnancy. In such children, surgery to remove the lesion may be curative. Working with the Epilepsy Surgery unit at the Royal Children’s Hospital we are applying new molecular technologies such as deep sequencing, single-cell omics and 3D fluorescent imaging to brain tissue resected at surgery to understand the underlying mechanisms of seizure generation and to improve surgical and clinical management.
Beta-propeller Protein-Associate Neurodegeneration (BPAN)
BPAN is a rare, genetic disorder of the brain characterised by intellectual disability and seizures in early childhood followed by Parkinsonism and dystonia in adulthood. Individuals affected by BPAN exhibit build-up of iron in the brain.
BPAN is caused by mutations in the WDR45 gene which encodes the WD repeat-containing protein 45. The protein plays an important role in autophagy, a biochemical mechanism that regulates degradation and recycling of cellular components. However, very little is known about the cellular effects of mutations in WDR45 gene on the nervous system and how it causes BPAN. Hence, there are no drugs available that can cure or slow the progression of BPAN. In this project, we used patient-derived stem cells (iPSC) to study the effect of a mutation in the WDR45 gene on iron metabolism and autophagy. The stem cells were used to generate nerve cells that we can use to study disease-specific mechanisms and later test potential drug treatments. This new type of preclinical ‘brain in a dish’ model provides an exciting avenue to screen potential drugs before the initiation of clinical trials.
Understanding the molecular basis of CANVAS – a novel neurological disorder caused by an expanded DNA repeat
Repeat expansions cause over twenty neurogenetic disorders of major clinical significance which can present with heterogenous, overlapping clinical phenotypes. Collectively repeat expansion disorders are the most common genetic conditions seen by neurologists.
Recently, we identified the expanded repeat causing cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS). Our preliminary studies suggest the expansion is the most common genetic cause of ataxia in humans. However, limited information is currently available regarding repeat size and composition, and how these influence clinical phenotype. This project will characterise the CANVAS repeat mutation using various Next Generation sequencing technologies. We also use patient-derived stem cells to study the effects of the repeat on nerve cells to determine the underlying pathogenic mechanism(s) causing CANVAS. The detailed knowledge generated will enable phenotype-genotype correlations to both guide future clinical care and identify potential therapeutic targets.
Determining the genetic basis of Malformations of Brain Development
Malformations of brain development (MBDs) are relatively common disorders causing epilepsy, cerebral palsy, and developmental delay in children. Greater than 1500 Australian children per year are born with an MBD and tens of thousands of living Australians are affected.
Genetic causes are thought to underlie the majority of MBDs, yet many causative genes remain to be identified. A genetic diagnosis provides important information for prognosis, accurate genetic counselling, and diagnostic/prenatal testing. In addition, the analyses of individuals with MBDs can provide a greater understanding of brain function and development, enable genomic medicine and translate to specific therapeutics (precision medicine). This project utilises advanced genomic technologies, including Next Generation sequencing and single-cell omics approaches to identify the genes that cause MBD and understand the underlying processes that disrupt the normal formation of the brain during a child’s development.
Funding
- National Health and Medical Research Council
- Medical Research Futures Fund
- Royal Children’s Hospital Research Foundation
- The Orphan Disease Center (Million Dollar Bike Ride Grant Program)
- Stafford Fox Medical Research Foundation
- Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne
Collaborations
- Professor Melanie Bahlo, Walter Eliza Hall Institute
- Professor Matthew Farrer, University of British Columbia
- Professor Linda Richards, Queensland Brain Institute
- Professor Stephen Robertson, University of Otago
- Professor Ingrid Scheffer, Melbourne Brain Centre
- IRC5
Featured publications
- Heterozygous PNPT1 Variants Cause Spinocerebellar Ataxia Type 25. Barbier M et al. Ann Neurol. 2022 Jul;92(1):122-137. PMID: 35411967
- Germline variants in tumor suppressor FBXW7 lead to impaired ubiquitination and a neurodevelopmental syndrome. Stephenson SEM et al. Am J Hum Genet. 2022 Apr 7;109(4):601-617. PMID: 35395208
- Advancing the diagnosis of repeat expansion disorders. Lockhart PJ. Lancet Neurol. 2022 Mar;21(3):205-207. PMID: 35182498
- Bioinformatics-Based Identification of Expanded Repeats: A Non-reference Intronic Pentamer Expansion in RFC1 Causes CANVAS. Rafehi H et al. Am J Hum Genet. 2019 Jul 3;105(1):151-165. PMID: 31230722
- Mutations in DCC cause isolated agenesis of the corpus callosum with incomplete penetrance. Marsh AP et al. Nat Genet. 2017 Apr;49(4):511-514. PMID: 28250454