Matchmaking facilitates the diagnosis of an autosomal-recessive mitochondrial disease caused by biallelic mutation of the tRNA isopentenyltransferase (<i>TRIT1</i>
) gene

Kernohan, Kristin D.; Dyment, David A.; Pupavac, Mihaela; Cramer, Zvi; McBride, Arran; Bernard, Geneviève; Straub, Isabella R.; Tétreault, Martine; Hartley, Taila; Huang, Lijia; Sell, Erick; Majewski, Jacek; Rosenblatt, David S.; Shoubridge, Eric A.; Mhanni, Aziz; Myers, Tara; Proud, Virginia K.; Vergano, S Schrier; Spangler, Brooke B.; Farrow, Emily; Kussman, Jennifer; Safina, Nicole P.; Saunders, Carol J.; Boycott, Kym M.; Thiffault, Isabelle

doi:10.1002/humu.23196

Cited by 42 publications

(33 citation statements)

References 17 publications

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“…Genematching platforms have also been utilized to find a “match” for those with novel exome results in a single patient (the so‐called lonely exome). A match with another individual with the same or similar phenotype and variant in the same gene can potentially provide further evidence that the newly discovered candidate is responsible …”

Section: Focal Epilepsy Syndromesmentioning

confidence: 99%

“…A match with another individual with the same or similar phenotype and variant in the same gene can potentially provide further evidence that the newly discovered candidate is responsible. 191 For the diagnosis of epilepsy, NGS-based testing is often performed later in the individual's diagnostic odyssey. There is evidence that it is cost-effective to perform these genomic tests earlier, as it may reduce the overall costs associated with repeat specialist visits, repeat imaging (MRI) and EEGs as well as more invasive testing (muscle biopsy).…”

Section: Future Directionsmentioning

confidence: 99%

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Epilepsy genetics: Current knowledge, applications, and future directions

2018

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The rapid pace of disease gene discovery has resulted in tremendous advances in the field of epilepsy genetics. Clinical testing with comprehensive gene panels, exomes, and genomes are now available and have led to higher diagnostic rates and insights into the underlying disease processes. As such, the contribution to the care of patients by medical geneticists, neurogeneticists and genetic counselors are significant; the dysmorphic examination, the necessary pre- and post-test counseling, the selection of the appropriate next-generation sequencing-based test(s), and the interpretation of sequencing results require a care provider to have a comprehensive working knowledge of the strengths and limitations of the available testing technologies. As the underlying mechanisms of the encephalopathies and epilepsies are better understood, there may be opportunities for the development of novel therapies based on an individual's own specific genotype. Drug screening with in vitro and in vivo models of epilepsy can potentially facilitate new treatment strategies. The future of epilepsy genetics will also probably include other-omic approaches such as transcriptomes, metabolomes, and the expanded use of whole genome sequencing to further improve our understanding of epilepsy and provide better care for those with the disease.

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Section: Focal Epilepsy Syndromesmentioning

confidence: 99%

Section: Future Directionsmentioning

confidence: 99%

Epilepsy genetics: Current knowledge, applications, and future directions

2018

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“…It was noted that the i 6 A37-m 3 C 32 ASL modification circuit may have implications for disease as mutations in TRIT1, the gene responsible for i 6 A 37 formation on cytosolic and mitochondrial tRNAs, cause human pathology due in large part to mitochondrial dysfunction [145,146]. In humans i 6 A 37 is found on cytosolic tRNAs Ser and tRNA Ser[Sec] in addition to several mitochondrial tRNAs that contain i 6 A 37 or ms 2 i 6 A 37 among which is the major species tRNA Ser(UGA) [130] that also contains m 3 C 32 (also see [102,131]).…”

Section: Interdependence Of Position 37 Modifications In Eukaryalmentioning

confidence: 99%

Factors That Shape Eukaryotic tRNAomes: Processing, Modification and Anticodon–Codon Use

Maraia

Arimbasseri

2017

Biomolecules

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Transfer RNAs (tRNAs) contain sequence diversity beyond their anticodons and the large variety of nucleotide modifications found in all kingdoms of life. Some modifications stabilize structure and fit in the ribosome whereas those to the anticodon loop modulate messenger RNA (mRNA) decoding activity more directly. The identities of tRNAs with some universal anticodon loop modifications vary among distant and parallel species, likely to accommodate fine tuning for their translation systems. This plasticity in positions 34 (wobble) and 37 is reflected in codon use bias. Here, we review convergent evidence that suggest that expansion of the eukaryotic tRNAome was supported by its dedicated RNA polymerase III transcription system and coupling to the precursor-tRNA chaperone, La protein. We also review aspects of eukaryotic tRNAome evolution involving G34/A34 anticodon-sparing, relation to A34 modification to inosine, biased codon use and regulatory information in the redundancy (synonymous) component of the genetic code. We then review interdependent anticodon loop modifications involving position 37 in eukaryotes. This includes the eukaryote-specific tRNA modification, 3-methylcytidine-32 (m3C32) and the responsible gene, TRM140 and homologs which were duplicated and subspecialized for isoacceptor-specific substrates and dependence on i6A37 or t6A37. The genetics of tRNA function is relevant to health directly and as disease modifiers.

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“…Mitochondrial activity of TRIT1 is relevant because pathogenic mutations to it that decrease i6A37 modification of both cy-tRNAs and mt-tRNAs, manifest in patients principally as mitochondrial insufficiency due to impairment of the mitochondrial translational system [41] [also see 54]. We should note that the majority of pathogenic SNPs in TRIT1 described [41, 54], do not reside within or near the MTS examined here, (one allele of a compound heterozygous genotype predicts a truncation at Arg-8) [54]. Examining the N-terminal MTS was also important because a popular algorithm predicts presequence cleavage at position 47 which would remove residues critical for modification activity, including the conserved P-loop containing the invariant catalytic T32, which we showed is required for efficient modification activity of cy- and mt-tRNAs.…”

Section: Discussionmentioning

confidence: 99%

“…Mt-IPTase deficiency is linked to C. elegans longevity [53]. Mutations in TRIT1 cause neurodevelopmental disorder [41, 54]. In this case, most if not all pathophysiology is attributable to hypomodification of mt-tRNA and impairment of mitochondrial translation and oxidative phosphorylation, even though the cy-tRNAs are also hypomodified [41].…”

Section: Introductionmentioning

confidence: 99%

Targeting of mitochondrial and cytosolic substrates of tRNA isopentenyltransferases: selection of differential tRNA-i6A37 identity subsets

Khalique

Mattijssen

Haddad

et al. 2019

Preprint

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ABSTRACTtRNA isopentenyltransferases (IPTases), which add an isopentenyl group to N6 of adenosine-37 (i6A37) of certain tRNAs, are among a minority of modification enzymes that act on both cytosolic and mitochondrial substrates. The Caenorhabditis elegans mitochondrial IPTase impacts life expectancy, and pathogenic mutations to human IPTase (TRIT1) that decrease i6A37 levels cause mitochondrial insufficiency and neurodevelopmental disease. Understanding of IPTase broad function should consider the differential identities of the tRNAs selected for i6A37 formation and their cognate codons, which vary among species in both their nuclear- and mitochondria-encoded tRNAs. Substrate selection is principally by recognition of the A36-A37-A38 sequence but can be negatively impacted by certain anticodons, and by ill-defined properties of the IPTase. Thus, tRNAs-i6A37 comprise a modification code system whose principles are incompletely understood. While Saccharomyces cerevisiae uses alternative translation initiation to target IPTase to mitochondria, our analyses indicate that TRIT1 uses a single initiation site to produce a mitochondrial targeting sequence (MTS) that we demonstrate by point mutagenesis using GFP imaging in human cells. We also examined cytosolic and mitochondrial tRNA modification by TRIT1 in Schizosaccharomyces pombe using tRNA-mediated suppression and i6A37-sensitive northern blotting. The TRIT1 MTS mutations indeed decrease mitochondrial-tRNA modification in S. pombe. We also show TRIT1 modification deficiency specific for tRNATrpCCA despite A36-A37-A38, consistent with the negative effect of the CCA anticodon as was described for Mod5 IPTase. This TRIT1 deficiency can be countered by over-expression. We propose a model of tRNA-i6A37 identity selection in eukaryotes that includes sensitivity to substrates with YYA anticodons.AUTHOR SUMMARYtRNA isopentenyltransferases (IPTases) are tRNA modification enzymes that are conserved in bacteria and eukaryotes. They add an isopentenyl group to the Adenosine base at position 37, adjacent to the anticodon of specific subsets of tRNAs that decode codons that begin with Uridine. This modification stabilizes the otherwise weak adjacent codon-anticodon basepair and increases the efficiency of decoding of the corresponding codons of the genetic code. IPTases belong to a group of enzymes that modify both cytoplasmic and mitochondrial tRNAs of eukaryotic cells. Interestingly, during evolution there were changes in the way that IPTases are targeted to mitochondria as well as changes in the relative numbers and identities of IPTase tRNA substrates in the cytoplasm vs. mitochondria, the latter consistent with phenotypic consequences of IPTase deficiencies in fission and budding yeasts, and mammals. Pathogenic mutations to human IPTase (TRIT1) cause mitochondrial insufficiency and neurodevelopmental disease, principally due to decreased modification of the mt-tRNA substrates. In this study, we identify the way human TRIT1 is targeted to mitochondria. We also show that TRIT1 exhibits a tRNA anticodon identity-specific substrate sensitivity. The work leads to new understanding of the IPTases and the variable codon identities of their tRNA substrates found throughout nature.

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Matchmaking facilitates the diagnosis of an autosomal-recessive mitochondrial disease caused by biallelic mutation of the tRNA isopentenyltransferase (TRIT1 ) gene

Cited by 42 publications

References 17 publications

Epilepsy genetics: Current knowledge, applications, and future directions

Epilepsy genetics: Current knowledge, applications, and future directions

Factors That Shape Eukaryotic tRNAomes: Processing, Modification and Anticodon–Codon Use

Targeting of mitochondrial and cytosolic substrates of tRNA isopentenyltransferases: selection of differential tRNA-i6A37 identity subsets

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