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Mutations in GTPBP3 Gene Cause Severe Mitochondria-Based Disease

Diseases of dysfunctional mitochondria are relatively rare, with a prevalence of 1/2000-4000. They predominantly affect children, however adult-onset disorders are also recognized. An international collaborative effort of fifteen clinical and/or research centers 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 the Institute of Human Genetics, Helmholtz Centre in Munich resulted in the discovery that mutations in the GTPBP3 (GTP-binding protein 3) 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. The research was reported in the December 4, 2014 issue of the American Journal of Human Genetics in an open-access article. 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.

Identification of mutations in nine unrelated families makes GTPBP3 an important new genetic factor responsible for human mitochondrial disease.

The researchers said, “We have analyzed 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.”

“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 provide 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.”

The GTPB3 gene is located on human chromosome 19.

[Press release] [AJHG article]