Neurogenetic Research (BLC)

The Neurogenetic Research 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. A major focus of the group’s research is gene discovery and functional characterisation of proteins contributing to neurodevelopmental and neurogenetic disorders including autism, brain malformations, Parkinson's disease and ataxia.

The team uses powerful modern genomic technologies, including high density SNP arrays and massively parallel sequencing, to identify changes in genes that cause disease. 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, the potential for pre-implantation genetic diagnosis and potentially targeted treatments or therapeutics. The group’s studies aim to understand mechanisms underlying disease and are an essential prerequisite for the development of treatment programs as well as prevention or onset-delay strategies for brain and mind disorders.

Group Leaders: 
Group Members: 
Kate Pope
Role: 
Clinical Research Coordinator
Greta Gillies
Role: 
Research Assistant
Sarah Stephenson
Role: 
Postdoctoral Fellow
Ashley Marsh
Role: 
Postgraduate Scholar
Hwee Ong
Role: 
Postgraduate Scholar
Dean Phelan
Role: 
Postgraduate Scholar
Chloe Stutterd
Role: 
Postgraduate Scholar
Yujing Gao
Role: 
Postgraduate Scholar

Accelerated Gene Identification Program (AGIP)
The aim of this program is to use modern genetic technologies to identify and subsequently characterise disease-causing genes for genetic disorders. The experimental design involves a co-ordinated clinical/research pipeline, whereby individuals and families with genetic disorders are identified and characterised by units including the Brain Malformations Clinic at the Royal Children’s Hospital and Victorian Clinical Genetics Service at the MCRI. Modern genomic and bioinformatic technologies are used to identify the disease-causing gene. Subsequent experimental studies use a combination of molecular and biochemical characterisation of cell and animal models to investigate and understand the cause of the disorder. Recent successes include the identification of novel genes responsible for Borrone Syndrome, short rib polydactyly, cardiomyopathy and Parkinson’s disease.

Understanding the role of Parkin and PACRG in Parkinson’s disease
Parkinson’s disease (PD) is a significant burden to Australia and the developed world. The most common cause of early onset disease (before 50 years of age) is mutation in the parkin gene. The team previously showed a second gene called Parkin co-regulated gene (PACRG) is linked to parkin. The preliminary data suggests there is functional significance to this genomic arrangement. This project aims to generate novel mouse models dysregulated for Parkin and Pacrg and use these to investigate the functional relationship of the bidirectional Parkin-PACRG locus. We believe that understanding the regulation of these genes will enable a better understanding of what causes Parkinson’s disease.

Molecular studies of Friedrich ataxia
Friedreich ataxia (FRDA) is the most common inherited ataxia and usually begins in childhood. It causes progressive damage to the nervous system and wide-ranging symptoms, including unsteadiness, ultimately resulting in affected individuals requiring a wheelchair. In most individuals, FRDA also affects the heart, with increased thickness of the heart wall (cardiomyopathy) and a propensity to irregular heart rhythms, called arrhythmia. In FRDA, the altered gene is called FXN and this instructs cells to make the frataxin protein. A DNA expansion in FXN results in lower levels of frataxin protein in people with FRDA compared to unaffected individuals.
The overall goal of our research is to develop safe, efficient therapies and biomarkers for FRDA and other neurological diseases. Our ongoing projects are outlined here.

Cilia and human disease
Cilia are evolutionarily-conserved microtubule-based hair-like organelles that perform remarkably diverse cellular functions. A large and increasing number of genetic diseases are associated with defects in cilia, however, there is still limited understanding of the basic mechanisms, proteins and pathways regulating their formation, structure and function. The team has previously shown loss of the Parkin co-regulated gene (PACRG) in mice results in both hydrocephalus and infertility. Similarly, variation in the human gene is associated with human male infertility. This project uses cell and animal models to investigate the basic biology and function of PACRG in cilia and determine the role of PACRG-mediated cilial dysfunction in human disease.

Immunofluorescent studies detecting a ciliary marker (red) and PACRG (green) demonstrate a high degree of co-localisation (yellow) indicating that PACRG is a component of (A) the cilia specialised ependymal cells within the brain; (B) the cilia of the cells lining the trachea and (C) the tail of sperm.

Clinical and Molecular Genetic Study of Autism Spectrum Disorders
The Autism Spectrum Disorders (ASD) are a group of neuro-developmental disorders defined by impairment in language and social interaction. The disorders affect approximately one in 100 individuals. The researchers in this project are aiming to identify novel genes that contribute to ASD. They perform clinical phenotyping of large families with multiple affected members to identify families suitable for linkage analysis and gene discovery. Subsequent studies will investigate the role of identified genes in cohorts of patients with sporadic ASD and also study the gene function and pathogenic mechanisms using cell and animal models.

Determining the genetic control of Corpus Callosum development
Malformations of brain development (MBD) are a group of congenital brain abnormalities which are a significant cause of neurocognitive disabilities and neurological disorders. The routine use of imaging in both prenatal screening and the assessment of children with neurodevelopmental abnormalities have revealed that MBD are a frequent cause of disability in the paediatric population. As the awareness of MBD has increased so has research into the underlying pathogenic mechanisms and with this the recognition of the critical role genetics plays in regulating brain development. However, despite substantial progress made during the past decade, the majority of genes underlying human MBD remain unknown.

This project focuses on agenesis (partial or complete developmental absence) of the corpus callosum (ACC), a disorder that affects approximately one in 4,500 children in the general population and three to five per cent of individuals assessed for a neurodevelopmental disorder. The corpus callosum is composed of approximately 200 million axons connecting the left and right sides of the brain. The CC functions by transferring and integrating information between the two halves of the brain. ACC is a genetically complex, congenital disorder associated with intellectual disability and neurological deficits such as developmental delay and seizures. The project aims to identify and characterise genes underlying ACC using modern genomic technologies and cell and animal models. Completion of this project will reveal fundamental mechanisms regulating CC development and function and will provide insights into normal brain development.

Sagittal T2-weighted brain MRI scans. A) A newborn with an intact corpus callosum.  B) A child with complete loss of the corpus callosum.
Funding: 
  • NHMRC Project grant 1098255, 2016-2020, Understanding the Neurobiology of Autism Spectrum Disorder (CIs: Scheffer, Lockhart, Delatycki, Wilson, Fanjul, Stanley)
  • NHMRC Project grant 1102207, 2016-2018, A randomised placebo-controlled crossover trial of micronised resveratrol as a treatment for Friedreich ataxia (CIs: Delatycki, Yiu, Corben, Cranswick, Lockhart, Wilmot, Lamont, O’Sullivan)
  • NHMRC Project grant 1059666, 2014-2016,  Determining the genetic control of Corpus Callosum development (CIs: Lockhart, Leventer, Amor, Delatycki)
  • Brain Foundation Australia grant, 2016, Using brain tissue to find the causes of epilepsy (CIs: Leventer, Lockhart)
  • Campbell Edwards Trust, 2015-2016, Understanding brain malformations in childhood (CIs: Leventer, Lockhart)
  • NHMRC Project grant 1041860, 2013-2015, Functional characterisation of a new gene for Parkinson's disease (CIs: Lockhart, Mellick, Amor, Delatycki)
  • NHMRC Project grant 1044175, 2013-2015, Genetics of Autism (CIs: Scheffer, Lockhart, Delatycki, Wilson)
  • NHMRC Project grant 1046206, 2013-2015, Functional analysis of protein turnover pathways (CIs: Lockhart, Farrer)
  • APA Postgraduate scholarship, 2013-2015 (Marsh)
Collaborations: 
  • Associate Professor Melanie Bahlo, Walter Eliza Hall Institute
  • Professor Matthew Farrer, University of British Columbia
  • Professor Glenda Halliday, Neuroscience Research Australia
  • Associate Professor George Mellick, Griffith University
  • Professor Linda Richards, Queensland Brain Institute
  • Professor Stephen Robertson, University of Otago
  • Professor Ingrid Scheffer, Melbourne Brain Centre