Two MCRI researchers win major awards for advancing the fight against complex genetic disease

Mitochondrial disease starves the body's cells of energy, resulting in multiple organ dysfunction and failure. There is no cure and few effective treatments for mitochondrial disease, which can cause any symptom in any organ at any age and is now second only to cystic fibrosis as the most commonly diagnosed serious genetic disease.

AMDF CEO Sean Murray presented Drs Alison Compton and Ann Frazier with AMDF Awards for Excellence in Mitochondrial Research, which recognise exemplary work in the rapidly evolving field of mitochondrial medicine.

"We applaud and thank our 19 AMDF Award winners – community advocates, volunteers, donors, fundraisers, doctors and researchers – for their passion, commitment and significant contributions to the mitochondrial disease cause and the mito community around Australia," he said.

Dr Alison Compton – Murdoch Children's Research Institute
Biallelic Mutations in TMEM126B Cause Severe Complex I Deficiency with a Variable Clinical Phenotype

Establishing a genetic diagnosis in people with mitochondrial disease can be challenging. Mitochondrial disease can be caused by mutations in more than 280 genes and is further complicated by multiple modes of possible inheritance. Previously, we could only test for mutations in one gene at a time. However, massively parallel sequencing technologies have been transformative in this field; resulting in increased numbers of definitive diagnoses as well as shortened diagnosis times. However, many people still remain without a genetic diagnosis. It is thought that many potential diagnoses may lie in poorly understood or yet uncharacterised genes, and are reliant on better characterisation of these orphan genes.

Recently we identified the orphan gene, TMEM126B as a cause of mitochondrial disease presenting as a late-onset myopathy with intellectual sparing. TMEM126B is a protein required for the correct assembly of mitochondrial complex I. Nine patients have now been identified with mutations in this gene, all of which inherited at least one copy of a common European mutation. We estimate that this mutation is carried by 1 in 500 - 1000 people of European background in contrast to 1 in 10,000 people of non-European populations. Mutations in TMEM126B should be considered for genetic testing in patients with a later-onset myopathy particularly in people of European background.

Dr Ann Frazier – Murdoch Children's Research Institute
ATAD3 gene cluster deletions cause cerebellar dysfunction associated with altered mitochondrial DNA and cholesterol metabolism

Mitochondrial disorders are complicated not only by the diversity of symptoms, but by the number of genes involved. While identification of causative gene mutations has benefited in recent years from advances in DNA sequencing technologies, some genomic regions have remained difficult to analyse. Furthermore, once a disease causing gene is identified, researchers are tasked with understanding the underlying disease mechanisms. 

Our recent publication, resulting from an international collaboration involving researchers and clinicians from Australia, UK, Netherlands, France and Japan, describes the identification and characterization of 6 patients from 5 families with DNA deletions and rearrangements affecting the complicated and highly repetitive ATAD3 gene locus. All patients presented with an array of neurological and other symptoms ranging from mild to severe, and our results indicate that ATAD3 mutations can be identified by targeted analysis of the ATAD3 locus, despite the complexity of the region. Significantly, using cell lines from the patients, we identified links between ATAD3, mtDNA and cholesterol, thus providing a mechanism for the disease symptoms that may have wider relevance to other neurological disorders.