Gene linked to mitochondrial disease will aid diagnosis

An international team of researchers has identified the genetic basis of a rare but fatal type of mitochondrial disease. The findings will help doctors to more accurately diagnose the disease and determine who does not have it.

Mitochondria are structures inside our cells that produce the energy needed to power our bodies. They carry their own genetic information, known as mitochondrial DNA, which is inherited solely from the mother. Although this encodes many of the genes they need to perform their function, mitochondria also rely on genes carried in the nucleus of the cell that are inherited from both parents.

Defects in mitochondrial DNA and/or nuclear DNA can have devastating effects on mitochondrial function, resulting in profound physical and intellectual disability and often death; however, the genetic causes of many mitochondrial diseases remain unknown.

The study, co-led by researchers at the Wellcome Trust Centre for Mitochondrial Research at Newcastle University and Baylor College of Medicine in the USA, looked at three unrelated families of Arabian origin who had been affected by a mitochondrial disease with similar symptoms. The team sequenced the entire genetic material, both nuclear and mitochondrial DNA, of one affected individual from each of the families.

Their findings identified mutations in a gene called FBXL4 as a primary cause of mitochondrial disease. Each child carried a slightly different mutation, but the effects were the same: profound defects in mitochondrial function, including a disturbance in the maintenance of mitochondrial DNA.

In two of the children, the effects of the mutation were so severe that both died before the age of two. The third child carried a less deleterious mutation and – although still severely affected – was alive at the last clinical check-up aged six.

The FBXL4 gene is encoded in the nuclear DNA. The inheritance patterns within the affected families reveal that it is recessive, meaning that two copies of the defective gene are needed to cause disease (one from each parent).

Professor Rob Taylor, a researcher at the Wellcome Trust Centre for Mitochondrial Research and lead author on the study, said: "Sadly, many families affected by mitochondrial diseases never find out the genetic causes of the condition, and we are unable to provide a diagnosis which could enable prenatal testing.

"We're hopeful that this finding will help to speed diagnosis in other families and will also help us to reassure those who do not carry this particular mutation. We're also interested to find out the precise role the FBXL4 protein plays in helping mitochondria function normally, an ongoing focus of research."

When the researchers grew cells from the affected patients in the laboratory, they were able to correct the mitochondrial defect by putting a healthy copy of the FBXL4 gene back into the cells.

Dr Penelope Bonnen, Assistant Professor of Molecular and Human Genetics at Baylor College of Medicine and the first author of the report, added: "Even when a genetic finding does not immediately translate into a treatment, families take some solace in knowing the diagnosis. They can finally end the search."

The study is published this week in the 'American Journal of Human Genetics'.

Bonnen PE et al. Mutations in FBXL4 cause mitochondrial encephalopathy and a disorder of mitochondrial DNA maintenance. Am J Hum Genet 2013 [epub ahead of print].