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Defective iA37 Modification of Mitochondrial and Cytosolic tRNAs Results from Pathogenic Mutations in TRIT1 and Its Substrate tRNA


Mitochondrial disorders are clinically diverse, and identifying the underlying genetic mutations is technically challenging due to the large number of mitochondrial proteins. Using high-throughput sequencing technology, we identified a disease-causing mutation in the TRIT1 gene. This gene encodes an enzyme, tRNA isopentenyltransferase, that adds an N6-isopentenyl modification to adenosine-37 (i6A37) in a small number of tRNAs, enabling them to function correctly during the synthesis of essential mitochondrial proteins. We show that this mutation leads to severe deficiency of tRNA-i6A37 in the patient's cells that can be rescued by introduction of the wild-type TRIT1 protein. A deficiency in oxidative phosphorylation, the process by which energy (ATP) is generated in the mitochondria, leads to a mitochondrial disease presentation. Introducing the mutant protein into model yeast species and measuring the resulting impairment provided further evidence of the pathogenic effect of the mutation. Additional studies investigating a previously reported pathogenic mutation in a mitochondrial tRNA gene demonstrated that a mutation in a substrate of TRIT1 can also cause a loss of the modification, providing evidence of a new mechanism causing mitochondrial disease in humans.


Vyšlo v časopise: Defective iA37 Modification of Mitochondrial and Cytosolic tRNAs Results from Pathogenic Mutations in TRIT1 and Its Substrate tRNA. PLoS Genet 10(6): e32767. doi:10.1371/journal.pgen.1004424
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004424

Souhrn

Mitochondrial disorders are clinically diverse, and identifying the underlying genetic mutations is technically challenging due to the large number of mitochondrial proteins. Using high-throughput sequencing technology, we identified a disease-causing mutation in the TRIT1 gene. This gene encodes an enzyme, tRNA isopentenyltransferase, that adds an N6-isopentenyl modification to adenosine-37 (i6A37) in a small number of tRNAs, enabling them to function correctly during the synthesis of essential mitochondrial proteins. We show that this mutation leads to severe deficiency of tRNA-i6A37 in the patient's cells that can be rescued by introduction of the wild-type TRIT1 protein. A deficiency in oxidative phosphorylation, the process by which energy (ATP) is generated in the mitochondria, leads to a mitochondrial disease presentation. Introducing the mutant protein into model yeast species and measuring the resulting impairment provided further evidence of the pathogenic effect of the mutation. Additional studies investigating a previously reported pathogenic mutation in a mitochondrial tRNA gene demonstrated that a mutation in a substrate of TRIT1 can also cause a loss of the modification, providing evidence of a new mechanism causing mitochondrial disease in humans.


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Genetika Reprodukčná medicína

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PLOS Genetics


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