Neurogenetic diseases


Current research projects

The research of the Neurogenetic Diseases Laboratory is divided into four principal themes:

 
Disease Gene Discovery 

The Neurogenetic Diseases Laboratory has been hunting human disease genes for nearly thirty years, identifying 25 novel human disease genes. We started analysing large Australian families with dominantly inherited neurological and neurogenetic disorders, making world first discoveries. These discoveries led to DNA samples being sent to us from around the world for the diseases that we had identified genes for and this continuing influx of samples in turn has led to further breakthroughs. The fact is, that in Australia, there are many large families with dominant diseases because of founder effects, where one person carrying a dominant mutation has emigrated to Australia, stayed in this wonderful country and had large families, with many descendants that we can trace. In order to find the genes for dominant human diseases, you have to study large families, so it follows that in many ways Australia is an ideal country in which to study dominant diseases. It also means that we are able to carry out studies that other groups around the world cannot. This has allowed us over the years to break new ground. As an example, Western Australia has one of the largest inherited familial amyotrophic lateral sclerosis (FALS) (otherwise known as motor neurone disease) families in the world. This family helped identify the superoxide dismutase gene (SOD1) in 1993 as the first known gene for FALS. 

In 1995 we obtained the first ever linkage for any distal myopathy in a large Western Australian family. This family has an unusual form of distal myopathy in that it has childhood onset, whereas most dominant distal myopathies have adult onset. In 2004 we finally published that the gene was mutated slow-skeletal/beta-cardiac myosin (MYH7), which was a huge surprise to the muscle research community, since mutations in this gene had already been associated with cardiomyopathy. However, it is now perfectly clear that particular mutations in a particular region of that myosin cause this relatively skeletal-muscle specific disease, other mutations in the gene cause the skeletal muscle disease myosin storage myopathy, while most mutations in the gene cause cardiomyopathy. This work adds to the growing understanding that different mutations in one gene can cause different diseases.

In 1999 the Laboratory identified mutations in the skeletal muscle alpha-actin gene (ACTA1) as a cause of congenital myopathies. This initial publication described 15 different mutations in ACTA1 causing in different patients nemaline myopathy, intranuclear rod myopathy and actin aggregate myopathy – previously considered to be different diseases. We and others have to date found over 200 different mutations in ACTA1, which are curated by Professor Laing and Dr Nowak into the ACTA1 Locus Specific Database in the Leiden Muscular Dystrophy Pages (https://www.perkins.org.au/our-research/divisions/molecular-medicine-and-ageing/neurogenetic-diseases/acta1/)

The Neurogenetic Diseases Laboratory has thus coincidentally identified diseases of the two most fundamental proteins in muscle contraction - actin and myosin.

Development of improved diagnostics 

Over the next five years, as part of the Australian Genomic Health Alliance (AGHA) NH&MRC Targeted Call for Research into the Application of Genomics in Health, the Neurogenetic Diseases Laboratory will be participating in building diagnostic networks for inherited disorders across Australia. This will lead to improved percentages of patients receiving accurate molecular diagnosis of the precise disease-causing mutation in their family. This in turn will have unforeseeable long-term benefits in improving the health of Australians.

Development of clinically applicable therapies 

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 in the patients. Some of these patients were less severely affected that patients with single, dominant ACTA1 mutations. We discovered that the ACTA1 recessive patients had retained expression of cardiac 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.

Prevention of genetic disease 

Preconception carrier screening has proven in the past to be extremely effective in reducing the incidence of severe genetic disease. Preconception carrier screening has most often been performed in populations with high carrier frequencies of certain recessive diseases. The most notable examples are preconception 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 disease genes simultaneously in large numbers of subjects. The new technologies need to be explored as possible tools for preconception carrier screening. 

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