Home  >  Research  >  Labs  >  Molecular Medicine Division  >  NEUROGENETIC DISEASES

CURRENT RESEARCH PROJECTS

Project

Disease Gene Discovery

Project

Disease Gene Discovery

Project Outline

The Neurogenetic Diseases Group is continuously involved in the identification of novel human disease genes. We mostly research Australasian families with genetically undiagnosed diseases. Many of these families we research are families that do not receive a diagnosis following standard of care diagnostic testing by the Neurogenetic Unit in PathWest, which is an Australasian referral centre for molecular diagnosis of neuromuscular diseases. Analysing these unresolved families has led to the identification of multiple novel human disease genes. It has also led to the identification of severe recessive diseases associated with genes that had previously only been thought to be associated with mild dominant disease: mutation of SCN4A and TOR1A for example. Other families we analyse are from clinicians and laboratories around the world, who send us samples from patients with diseases that look clinically like diseases we have already found genes for. Although thousands of disease genes have been identified, thousands more and thousands of new phenotype associations remain to be identified. At any one time we have multiple disease gene projects running. These are usually in collaboration with multiple laboratories spanning the globe, with researchers in the Group spending time in the USA, Europe, UK. One publication, KLHL40, involved 55 authors in more than 30 institutions on four continents.

Project

Development of improved diagnostics

Project

Development of improved diagnostics

Project Outline

Although current next generation sequencing diagnostics obtain precise molecular diagnosis for many patients, many patients remain without a diagnosis. One of the current issues is the large number of genetic variants of uncertain significance that are identified upon sequencing patient DNA. These variants are variants where diagnostic laboratories cannot be sure whether or not they are causing the disease in the patient. To determine what variants are disease-causing requires the development of new diagnostic tools or new tools have to be imported from other centres and made to work in the Australian diagnostic setting. Functional analysis of variants is an increasing area of interest – analysing proteins containing the variant of uncertain significance to see if they behave like other known definitive disease-causing variant proteins. So many variants are identified that high throughput functional analysis tools need to be developed. Recognising the issues in genomics, the Australian Federal Government established in the 2018 Federal Budget the $500m Genomics Health Futures Mission, which is a Medical Research Future Fund (MRFF) funded project. The Neurogenetic Diseases Group will be participating in this project to improve rates of diagnosis of patients with genetic diseases.

Project

Development of treatments

Project

Development of treatments

Project Outline

In 2007, we showed that recessive skeletal muscle actin (ACTA1) disease is caused by loss of function mutations in the ACTA1 gene, leading to absence of skeletal muscle actin. Some of these patients were less severely affected than patients with single, dominant mutations in ACTA1. We discovered that the recessive patients retained expression of heart actin in their skeletal muscles after birth, whereas control subjects and patients with dominant ACTA1 mutations switch off cardiac actin in their skeletal muscles around birth. This suggested that cardiac actin was a target for therapy for the skeletal muscle actin diseases. A puzzle with children severely affected by mutations in the skeletal muscle alpha actin gene ACTA1 had been that eye movements remain unaffected even when other skeletal muscles were barely functional. In 2008 we showed that the extraocular muscles, the muscles that move the eyes, have high levels of cardiac actin, similar levels in fact to those in the heart. We postulated that it is this high level of cardiac actin that maintains function in the eye muscles. Thus, more than one line of evidence suggests pursuing cardiac actin as a viable therapy for the skeletal muscle actin diseases. We are pursuing multiple research avenues which could lead to clinically useful treatments for the actin and other muscle diseases.

Project

Reproductive carrier screening

Project

Reproductive carrier screening

Project Outline

Reproductive carrier screening introduced in the past to multiple communities has been associated with reduction in the incidence of severe genetic diseases. Reproductive carrier screening has most often been performed in populations with high carrier frequencies of certain recessive diseases. The most notable examples of this are carrier screening for Tay-Sachs disease in the Ashkenazi population and for thalassemia in Mediterranean countries. New genetic technologies make it possible to screen large numbers of known recessive disease genes simultaneously in large numbers of individuals. These new technologies need to be explored as tools for population-wide carrier screening. Health Minister Greg Hunt in the 2018 Federal Budget funded Mackenzie’s Mission: The Australian Reproductive Carrier Screening project, which is a $20m, three-year health services research project to to develop and test processes for implementing reproductive carrier screening, that could be scaled up to an Australia-wide level. The Project is expected to take 10 years to bring completely to fruition. Minister Hunt’s ultimate aim is to see reproductive carrier screening available to any Australian couple that wants to use it. The Neurogenetic Diseases Group is one of the three principal groups involved in the project which is being initiated in New South Wales, Victoria and Western Australia.

CURRENT STUDENT PROJECTS

Student project opportunities may be made available under any of the four research themes in the Group: Disease gene discovery, Development of improved diagnostics, Development of treatments, Reproductive carrier screening. We tailor the projects to the interests and skill sets of the prospective student.