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

2014/11/26 by Robert Kopajtich, Thomas J. Nicholls, Thomas J. Nicholls +62 · 163 citations
Biochemistry, Genetics and Molecular Biology · Medicine · #ATP Synthase and ATPases Research #Biology #Cardiomyopathy #Encephalopathy #Gene #Genetics #Heart failure #Hypertrophic cardiomyopathy #Internal medicine #Lactic acidosis #Medicine #Metabolism and Genetic Disorders #Mitochondrial Function and Pathology #Pathology #Translation (biology)

paper · pdf · doi:10.1016/j.ajhg.2014.10.017

published in The American Journal of Human Genetics 95(6), 708-720 (Elsevier BV)

openalex publication_date 2014/11/26 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/05

Abstract

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 (τm(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.

Citations

• Acute Infantile Liver Failure Due to Mutations in the TRMU Gene
• Missense Mutation in Pseudouridine Synthase 1 (PUS1) Causes Mitochondrial Myopathy and Sideroblastic Anemia (MLASA)

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