Mutations in GTPBP3 Cause a Mitochondria! Translation Defect Associated with Hypertrophic Cardiomyopathy, Lactic Acidosis, and Encephalopathy

作者：Kopajtich Robert; Nicholls Thomas J; Rorbach Joanna; Metodiev Metodi D; Freisinger Peter; Mandel Hanna; Vanlander Arnaud; Ghezzi Daniele; Carrozzo Rosalba; Taylor Robert W; Marquard Klaus; Murayama Kei; Wieland Thomas; Schwarzmayr Thomas; Mayr Johannes A; Pearce Sarah F; Powell Christopher A; Saada Ann; Ohtake Akira; Invemizzi Federica; Lamantea Eleonora; Sommerville Ewen W; Pyle Angela; Chinnery Patrick F; Crushell Ellen; Okazaki Yasushi; Kohda Masakazu

来源：American Journal of Human Genetics, 2014, 95(6): 708-720.

DOI：10.1016/j.ajhg.2014.10.017

Respiratory chain deficiencies exhibit a wide variety of clinical phenotypes resulting from defective mitochondrial energy production through oxidative phosphorylation. These defects can be caused by either mutations in the mtDNA or mutations in nuclear genes coding for mitochondrial proteins. The underlying pathomechanisms can affect numerous pathways involved in mitochondrial physiology. By whole-exome and candidate gene sequencing, we identified 11 individuals from 9 families carrying compound heterozygous or homozygous mutations in GTPBP3, encoding the mitochondrial GTP-binding protein 3. Affected individuals from eight out of nine families presented with combined respiratory chain complex deficiencies in skeletal muscle. Mutations in GTPBP3 are associated with a severe mitochondrial translation defect, consistent with the predicted function of the protein in catalyzing the formation of 5-taurinomethyluridine (tau m(5)U) in the anticodon wobble position of five mitochondrial tRNAs. All case subjects presented with lactic acidosis and nine developed hypertrophic cardiomyopathy. In contrast to individuals with mutations in MTO1, the protein product of which is predicted to participate in the generation of the same modification, most individuals with GTPBP3 mutations developed neurological symptoms and MRI involvement of thalamus, putamen, and brainstem resembling Leigh syndrome. Our study of a mitochondrial translation disorder points toward the importance of posttranscriptional modification of mitochondrial tRNAs for proper mitochondrial function.

• 出版日期2014-12-4
• 单位河北医科大学