In next-gen DNA sequence, new answers to a rare and devastating disease

September 6, 2011, Cell Press

In Leigh syndrome, infants are born apparently healthy only to develop movement and breathing disorders that worsen over time, often leading to death by the age of 3. The problem is that the mitochondria responsible for powering their cells can't keep up with the demand for energy in their developing brains.

Now, researchers reporting in the September issue of , a Cell Press publication, have discovered a new genetic defect that can lead to the disease. The findings were made by sequencing a subset of about 1,000 genes encoding proteins active in the mitochondria in just two individuals with Leigh syndrome.

"This shows the huge potential of to improve diagnosis," says David Thorburn of Murdoch Childrens Research Institute in Australia. "It's an all-comers approach that can be applied to individuals, even with no family history."

Leigh syndrome is the most common recognized mitochondrial disease of childhood, and the new genetic discovery adds to a growing list of about 40 genes known to cause Leigh syndrome when mutated.

The gene they uncovered encodes an enzyme active in mitochondria known as MTFMT (for mitochondrial methionyl-tRNA formyltransferase). (Mitochondria carry DNA of their own and their operation depends on a combination of proteins encoded locally and others encoded in the of a cell and imported.)

The MTFMT enzyme encoded in the is responsible for converting a (tRNA) into a form used to initiate protein translation. Without that enzyme, mitochondria fail to translate proteins efficiently leading to the symptoms recognized as Leigh syndrome. Studies in patient showed that the defects in translation could be corrected by replacing the MTFMT gene.

Although it isn't clear in the case of Leigh syndrome whether a precise will necessarily lead to therapies, the current findings represent a meaningful advance.

"It can be very reassuring to families to have a definitive answer," Thorburn says. "They are often referred around from one doctor to another. A diagnosis at least provides some closure to the diagnostic odyssey even without a treatment."

Diagnosis of the disease along with its specific genetic cause can also be informative about the risk a couple has of having another affected child, he adds. The diagnostic information can help in decisions about whether and how to pursue alternative means of having children, for instance through the use of donor sperm or eggs.

In addition to their clinical implications, the new findings offer insight into the biology and evolution of human mitochondria. Mitochondria originated from bacteria that were engulfed by another cell, and their use of the modified tRNA to initiate translation is a relic of that microbial past.

"It's not clear why this requirement would have been maintained," Thorburn says. "It means that if mitochondrial proteins enter the circulation, say after a traumatic injury, they are mistaken for bacterial proteins, triggering a systemic inflammatory response."

Explore further: Genetic map reveals clues to degenerative diseases

Related Stories

Genetic map reveals clues to degenerative diseases

August 24, 2011
An international research team, spearheaded by Dr. Tim Mercer from The University of Queensland's Institute for Molecular Bioscience (IMB), has unlocked the blueprints to the ‘power plants' of the cell in an effort that ...

Recommended for you

Blood-vessel-on-a-chip provides insight into new anti-inflammatory drug candidate

January 15, 2018
One of the most important and fraught processes in the human body is inflammation. Inflammatory responses to injury or disease are crucial for recruiting the immune system to help the body heal, but inflammation can also ...

Molecule produced by fat cells reduces obesity and diabetes in mice

January 15, 2018
UC San Francisco researchers have discovered a new biological pathway in fat cells that could explain why some people with obesity are at high risk for metabolic diseases such as type 2 diabetes. The new findings—demonstrated ...

Obese fat becomes inflamed and scarred, which may make weight loss harder

January 12, 2018
The fat of obese people becomes distressed, scarred and inflamed, which can make weight loss more difficult, research at the University of Exeter has found.

Optimized human peptide found to be an effective antibacterial agent

January 11, 2018
A team of researchers in the Netherlands has developed an effective antibacterial ointment based on an optimized human peptide. In their paper published in the journal Science Translational Medicine, the group describes developing ...

Research discovers possible link between Crohn's and Parkinson's in Jewish population

January 11, 2018
Mount Sinai Researchers have just discovered that patients in the Ashkenazi Jewish population with Crohn's disease (a chronic inflammatory of the digestive system) are more likely to carry the LRRK2 gene mutation. This gene ...

Scientists use gene expression to understand how astrocytes change with age

January 11, 2018
Potentially explaining why even healthy brains don't function well with age, Salk researchers have discovered that genes that are switched on early in brain development to sever connections between neurons as the brain fine-tunes, ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.