On this page:

• Research program
• Research support (2008/09)

Research program

• Gene discovery in inherited myopathies
• Disease mechanism in muscular dystrophies and membrane repair for therapy
• Skeletal muscle and athletic performance
• Learning disability and treatments
• Clinical trials and quality of life research
• Neuroinflammation

Gene discovery in inherited myopathies

Group Leaders: Dr Nigel Clarke and Dr Bilijana Ilkovski

The congenital myopathies are a group of inherited muscle disorders in which muscle weakness is usually generalised, present from birth and relatively static over time. The key investigation for diagnosis is the muscle biopsy. Many of the genes that cause the congenital myopathies remain to be discovered and much is unknown about how a mutation in a particular gene results in weakness. Our goal is to understand how a single mutation in a muscle gene (such as actin or tropomyosin) affects muscle architecture, energy use by the cell, calcium signals and force generation in the contractile structures. In a nutshell, we would like to understand the most important elements that contribute to muscle dysfunction to identify the best targets for therapy.

A second major focus of the team is a form of congenital myopathy called Congenital Fibre Type Disproportion (CFTD). Several significant challenges present for clinicians who care for patients with CFTD. The genetic basis in over 50% of families is unknown, the clinical patterns of disease are poorly defined and the most appropriate approach to establishing a genetic diagnosis is unclear. There is little understanding how and why generalized type 1 fibre hypotrophy arises and its relationship to the significant, sometimes lethal, muscle weakness – even though type 1 fibre atrophy is a common feature in many inherited muscle disorders. We are world leaders in identifying the genetics causes of CFTD (eg. TPM3, ACTA1, RYR1) and are referred patients for diagnosis from around the world. Ongoing studies focus on finding the remaining genetic causes, and the biological processes that underlie the altered fibre growth.

Disease mechanism in muscular dystrophies and membrane repair for therapy

Group Leader: Dr Sandra Cooper

Deficiency of dysferlin causes one of the most common forms of autosomal recessive muscular dystrophy (LGMD 2B). The basis for muscle degeneration and weakness in dysferlinopathy is due to a primary defect in the ability of skeletal muscle fibres to repair lesions in their surface membranes following injury. Many forms of muscular dystrophy are associated with a structural fragility of the muscle membrane, whereby membrane damage exceeds the ability of muscle to repair itself, resulting in the progressive degeneration of muscle fibres. We are studying a new form of muscular dystrophy caused by mutations in the gene dysferlin. Rather than having a structural role, dysferlin has recently been shown to play a role in repairing the small sites of membrane damage caused through normal physical activity. In dysferlin patients, the structure of the membrane is normal, but membrane repair is impaired.

There are many patients with muscular dystrophy in whom the genetic basis for their disorder is unknown. It is likely that some of these patients have defects in other proteins that interact with dysferlin and/or are involved in membrane repair pathways.

Skeletal muscle and athletic performance

Group Leader: Dr Nan Yang

The existence of a common genetic variant that influences human muscle function has implications for health and fitness across the human lifespan. The α-actinins are a major structural component of skeletal muscle.

The INMR's discovery of the skeletal muscle gene alpha-actinin-3 and its association with human athletic performance was selected by Discovery Magazine as one of the Top 100 Science Stories of 2003. The INMR, using data gathered from patients, sprint and endurance athletes and a number of populations around the world, as well as from a mouse model developed within the laboratory, has demonstrated that the absence of alpha-actinin 3 (in over one billion individuals worldwide) is associated with lower muscle strength and is detrimental to sprint performance and power activities. The phenotypic consequences of alpha-actinin-3 deficiency, including reduced muscle mass and altered metabolic properties, may have important implications for public health to better understand the functional role of alpha-actinins in muscle and to apply this information to the study of variations in muscle function in health and disease.

We are in a unique position to investigate these mechanisms, having successfully generated an Actn3 knockout mouse, and gathered a team with experience in the study of protein-protein interactions, molecular evolution and mouse phenotype analysis, allowing us to take a novel and cross-disciplinary approach to this investigation.

Learning disability and treatments

Group Leader: Dr Jonathan Payne

Neurofibromatosis type 1 (NF1) is a common disorder affecting 1 in 3000 – the most common neurological complication is cognitive dysfunction. One of the most telling areas indicative of cognitive deficits in NF1 is academic achievement, with up to 70 percent of school-aged children with NF1 underachieving and learning disabilities estimated to be present in 30 to 65 percent of children. Areas of difficulty appear to encompass a range of academic skills including reading, spelling and mathematics, with no one area predominately more affected.

We are currently the lead and only site in Australia involved in an international Phase II clinical trial examining the efficacy and safety of lovastatin in treating visuospatial memory and attentional impairments in children with NF1.

In a world first, we are also currently conducting two longitudinal studies to tell us more about how children with NF1 develop, learn, and think, and identify the factors placing young children with NF1 at risk for cognitive difficulties. This will allow us to implement treatment strategies at appropriate ages and will guide the development of new treatments for children with NF1 who experience cognitive difficulties.

Clinical trials and quality of life research

Group Leader: Dr Joshua Burns

Our research has led to a number of significant health outcomes for patients, with the implementation of therapies through clinical trials that have resulted in improvement of life span for many patients by up to 15 years. The INMR is currently running three major trials, one of which is an international trial (the INMR is the only Australian site) involving children with Duchenne Muscular Dystrophy (DMD) to investigate if a form of steroid called Deflazacort can improve the quality of life for patients and lessen the side effects experienced with current medication. It is the availability of new medications and treatments through clinical trials that can provide enormous benefits for patients and their families.

The INMR has developed a comprehensive clinical trials program with more than eight (8) clinical trials currently being conducted for therapeutics options for neuromuscular disorders:

• Exercise and strength therapy for Charcot-Marie-Tooth (CMT) disease
• Curcumin for Déjerine-Sottas syndrome
• Trials of Deflazacort in DMD
• Tyrosine in nemaline myopathy
• Ascorbic acid and botulinum toxin in CMT disease
• Gene therapy with treatment by antisense oligonucleotides in patients with DMD in collaboration with Dr Steve Wilton in Perth

Neuroinflammation

Group Leaders: Dr Russell Dale and Dr Fabienne Brilot-Turville

Our research is dedicated to understanding the role of humoral immunity in inflammatory and autoimmune disorders of the central nervous system in children. We have particular interest in the following conditions:

• Brain demyelination and multiple sclerosis. We are studying the role of autoantibodies against myelin oligodendocyte glycoprotein in CNS demyelination.
• Autoimmune encephalitis. We have recently identified children with the newly described N-methyl-D-aspartate receptor (NMDAR) and voltage-gated potassium channel encephalitis. These patients have autoantibodies that bind to neurotransmitter receptors or ion channels. These disorders are acquired channelopathies.
• Autoimmune movement disorders. We are investigating the autoimmune mechanisms in Sydenham chorea, in movement disorders associated with systemic lupus erythematosus, and in Tourette syndrome.

Research support (2008/09)

• National
• International
• Local

National

Inherited muscle disorders- gene discovery, pathobiology and therapy
Laing N, North K N, Nowak K
NHMRC # 403941 ($1,677,500 over 5 yearss)

The role of aquaporins in cardiac ischaemia and reperfusion
Winlaw D S, North K N
NHMRC #512254. ($466,875 over 3 years)

Molecular dissection of the effects of alpha-actinin-3 deficiency on normal variations in skeletal muscle function
North K N, Huttley G A, Cooney G J
ARC Discovery Project Grant # DP0880844 ($432,776 over 3 years)

Biolistic PDS-1000/Hepta Gene Transfer system
North K N, Cooper S
University of Sydney /NHMRC Equipment grant ($42,997 over 1 year)

Dysferlin muscular dystrophy and skeletal muscle membrane repair
Cooper S T, North K N
NHMRC Project Grant #570744 ($304,250 over 3 years)

Congenital Fibre Type Disproportion (CFTD): Disease patterns and pathogenesis of muscle weakness
Clarke N F, North K N, Ilkovski B
NHMRC Project Grant #571287 ($254,250 over 3 years)

International

The Role of Contactin-1 in severe childhood myopathy
North K N, Froehner S C
March of Dimes Birth Defects Foundation USA #6-FY08-219 ($US282, 850 over 3 years)

A Randomized Placebo-Controlled Study of Lovastatin in Children with Neurofibromatosis Type 1 (CHW- coordinating centre)
US Army Medical Research and Materiel Command Office of Congressionally Directed Medical Research Programs ($US2,668,042.06 over 4 years)

Identification of dysferlin domains mediating membrane repair
Jain Foundation
Cooper ST ($99, 400)

Unmasking Mitochondrial Respiratory Chain (RC) Disorders by Forced Myogenesis of Cultured Cells
Christodoulou J, Cooper S T
March of Dimes Birth Defects Foundation ($US263 000 over 3 years)

Local

Real-time amplification system (QPCR) and high resolution melt (HRM) - Gene Expression and Analysis Facility
North K N, Christodoulou J, Gunning P W, Byrne J
Clive and Vera Ramaciotti Equipment Grant ($30,000)

Diagnosis and Therapy of Muscular Dystrophies and Inherited Myopathies
SMILE Foundation ($100,000)

Deltavision Core Image Restoration System with QLM
Clarke C, Turville S, Murray R, Chircop (nee Fabro) M, Becker T, O'Neill G, Bendall L, Henderson B, Cunningham A, Robinson P, Tam P, Kefford R, North K, Reddel R, Rizos H, Miranda-Saksena M
University of Sydney Research Infrastructure (Major Equipment) Scheme ($100,000)

Deltavision Core Image Restoration System with QLM
Clarke C, Turville S, Murray R, Chircop (nee Fabro) M, Becker T, O'Neill G, Bendall L, Henderson B, Cunningham A, Robinson P, Tam P, Kefford R, North K, Reddel R
USyd/NHMRC Major Equipment Grant 2008/09 ($200,000 over 2 years)