New genetic analysis approach could improve diagnosis for mitochondrial disease


Dr David Stroud from Monash Biomedicine Discovery Institute

An international team of scientists, led by researchers at the  Monash Biomedicine Discovery Institute (BDI) and the Murdoch Children’s Research Institute (MCRI), have shown a new approach to genetic analysis could greatly improve diagnostic rates for children with baffling and often fatal mitochondrial diseases.

Mitochondrial diseases are devastating conditions affecting babies, older children and adults. UK baby Charlie Gard suffered from a form of the condition called mitochondrial DNA depletion syndrome, which ultimately cost him his life.

Mitochondria are the power plants of cells, breaking down molecules from sugars, fats and proteins to generate energy for the human body, like burning coal to produce electricity.

Until recently, diagnosis for mitochondrial diseases has been very slow with only about a quarter of patients receiving a genetic diagnosis. Current treatments are also unsatisfactory – for example, an unproven therapy for mitochondrial DNA depletion syndrome was behind a UK court’s decision for preventing Charlie Gard’s family from travelling to the US to access the treatment.

However, new diagnostic methods like whole exome sequencing – which can quickly and cheaply sequence a person’s entire genetic blueprint – means up to two-thirds of affected children can now be diagnosed.

However other approaches are needed to identify the difficult cases that continue to elude diagnosis.

Published last week in the American Journal of Human Genetics, research co-led by Monash BDI researcher Dr David Stroud and MCRI PhD student Nicole Lake found a new cause of mitochondrial disease, which affects the ability of the mitochondria to operate as the body’s power plant, converting food into energy.

Ms Lake said the research identified mutations in a gene called MRPS34, in six patients with the most common form of childhood mitochondrial disease, Leigh Syndrome, from Australia, France and the USA.

“A key approach was using quantitative proteomics. This process involves sampling all the proteins in a cell at once to identify any problems with the cellular machinery,” said Ms Lake.

“Using this technique, you get a snapshot of what’s happening in cells.”

The MRPS34 gene is one of 80 components of the mitochondrial protein synthesis machinery, known as the ‘mitoribosome’.

Co-lead author, Dr David Stroud, carried out the quantitative proteomics technique, examining cellular proteins in the patient’s cultured skin cells, versus healthy skin cells at the Monash BDI.

“This showed one half of the mitoribosome fell apart, meaning cells could not make the key proteins encoded by mitochondrial DNA”, said Dr Stroud.

“At the same time we could also measure the resulting defects in two of the five major components of the power plants that fuel the body’s energy. This is an amazing level of detail for a single diagnostic technique,” he said.

MCRI Chief Investigator, Professor David Thorburn said MRPS34 was the 25th mitochondrial disease gene discovered by scientists at MCRI and one of the first in the world to show that quantitative proteomics could play a key role in improving diagnostic rates to closer to 100 per cent.

“This approach will therefore help to end the diagnostic odyssey for families with children suspected of mitochondrial and other inherited diseases,” Professor Thorburn said.

“Early diagnosis improves the chance for early intervention. It can also provide the opportunity to enrol patients with mitochondrial diseases into clinical trials to test many new promising therapies that are in the pipeline, but not yet proven.”

Sean Murray, CEO of the Australian Mitochondrial Disease Foundation (AMDF), said that this was an exciting development, which boosted one of the AMDF’s major aims in improving diagnostic rates for families affected by mitochondrial disease.

“I’m particularly thrilled to see an outcome like this, as it has been partly supported by the hard work of AMDF fund-raisers through activities such as our ‘Bloody Long Walks’ and demonstrates the value of researchers engaging with the patient community,” Mr Murray said.

AMDF provided financial support through an Incubator Grant and scholarship top-up support to Nicole Lake. See bloodylongwalk.com.au

The research was published this week in the American Journal of Human Genetics. Read the full paper titled Biallelic Mutations in MRPS34 Lead to Instability of the Small Mitoribosomal Subunit and Leigh Syndrome

------------------------------------------------------------------------------

Animation: Loss of MRPS34 destabilises the mitoribosome