Mutations in GTPBP3 cause a mitochondrial translation defect associated with hypertrophic cardiomyopathy, lactic acidosis, and encephalopathy

Diseases of dysfunctional mitochondria (aka mitochondrial diseases) are relatively rare with prevalence of 1/2000-4000. They predominantly affect children, however adult-onset disorders are also recognized. International collaborative effort of fifteen clinical and/or research centres from the UK, Germany, Ireland, France, Belgium, Austria Italy, Israel and Japan led by Dr. Michal Minczuk from the MRC MBU in Cambridge and Dr. Holger Prokisch from Institute of Human Genetics, Helmholtz Centre in Munich resulted in the discovery that mutations in the GTPBP3 gene cause defects in protein synthesis in mitochondria and are associated with a devastating disease. The patients affected by this disease have deficiency in energy production and suffer from heart and neurological disease.

Mitochondria are compartments present in every cell of the body (except red blood cells) and are responsible for generating almost all of the energy needed by the body to sustain life and to grow. In mitochondria, energy is produced by a large number of proteins, which are manufactured according to a blueprint, the cell's DNA. Most of these proteins are encoded by DNA that is contained within the cell nucleus (nuclear DNA), however, the remaining portion is encoded within a small DNA molecule found inside mitochondria. This molecule is called mitochondrial DNA (mtDNA) or the mitochondrial genome. The mitochondrial DNA must be transcribed into RNA and the RNA translated into proteins. If the mitochondrial genome is not properly expressed, then mitochondrial proteins will not be properly made, and the cell will not be able to produce energy in a useful form.

International collaborative effort of fifteen clinical and/or research centres from the UK, Germany, Ireland, France, Belgium, Austria Italy, Israel and Japan led by Dr. Michal Minczuk from the MRC MBU in Cambridge and Dr. Holger Prokisch from Institute of Human Genetics, Helmholtz Centre in Munich resulted in the discovery that mutations in the GTPBP3 gene cause defects in protein synthesis in mitochondria and are associated with a devastating disease. The patients affected by this disease have deficiency in energy production and suffer from heart and neurological disease.

What is the significance of the finding?

Diseases of dysfunctional mitochondria (aka mitochondrial diseases) are relatively rare with prevalence of 1/2000-4000. They predominantly affect children, however adult-onset disorders are also recognized. Identification of mutations in nine unrelated families makes GTPBP3 an important new genetic factor responsible for human mitochondrial disease.

In lay terms how did you conduct the experiment(s)?

We have analysed patients' DNA samples and found changes (mutations) in the GTPBP3 gene. We found that cells taken from the patients were unable to properly produce proteins in their mitochondria. To confirm that the mutations that we identified in the GTPBP3 gene are responsible for the disease we have inactivated the gene in vitro in healthy cells. Inactivation of the gene in vitro caused these healthy cells to also be unable to properly synthetize proteins that are encoded in mtDNA.

What are the clinical implications of your finding(s)? How is this finding of interest to the general public?

Our research has identified a new gene, which is the cause of a severe, rare human disease. This widens the catalogue of human genes associated with severe metabolic disorders. The findings allow for diagnosis of other patients affected with this disease and provides an opportunity for prenatal diagnosis. Further studies of processes in which GTPBP3 is involved will help towards the understanding of human diseases that are linked to mitochondrial DNA expression and to develop new therapies.