Mutational Screening for Mitochondrial tRNA Mutations in 150 Children with High Myopia

Background: Myopia is a very common eye disease with an unknown etiology. Increasing evidence shows that mitochondrial dysfunction plays an active role in the pathogenesis and progression of this disease. Objectives: The purpose of this study was to analyze the relationship between mitochondrial tRNA (mt-tRNA) variants and high myopia (HM). Methods: The entire mt-tRNA genes of 150 children with HM, as well as 100 healthy subjects, were PCR-amplified and sequenced. To assess the pathogenicity, we used the phylogenetic conservation analysis and pathogenicity scoring system. Results: We identified six candidate pathogenic variants: tRNALeu (UUR) T3290C, tRNAIle A4317G, tRNAAla G5591A, tRNASer (UCN) T7501C, tRNAHis T12201C, and tRNAThr G15915A. However, these variants were not identified in controls. Further phylogenetic analysis revealed that these variants occurred at the positions, which were very evolutionarily conserved and may have structural-functional impacts on the tRNAs. Subsequently, these variants may lead to the impairment of mitochondrial translation and aggravated mitochondrial dysfunction, which play an active role in the phenotypic expression of HM. Conclusions: Our results suggested that variants in mt-tRNA genes were the risk factors for HM, which provided valuable information for the early detection and prevention of HM.

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Screening for Mitochondrial tRNA Mutations in 318 Patients with Dilated Cardiomyopathy

Human Heredity ◽

10.1159/000521615 ◽

2022 ◽

Author(s):

Yujuan Qi ◽

Zhenhua Wu ◽

Yaobang Bai ◽

Yan Jiao ◽

Peijun Li

Keyword(s):

Dilated Cardiomyopathy ◽

Mitochondrial Dysfunction ◽

Copy Number ◽

Mutational Analysis ◽

Unknown Etiology ◽

Trna Genes ◽

Mtdna Copy Number ◽

Mitochondrial Trna ◽

Mitochondrial Functions ◽

And Gender

Objectives: Dilated cardiomyopathy (DCM) is a complex cardiovascular disease with unknown etiology. Although nuclear genes play active roles in DCM, mitochondrial dysfunction was believed to be involved in the pathogenesis of DCM. The objective of this study is to analysis the association between mitochondrial tRNA (mt-tRNA) mutations and DCM. Material and Methods: We performed a mutational analysis of mt-tRNA genes in a cohort of 318 patients with DCM and 200 age- and gender-matched control subjects. To further assess their pathogenicity, phylogenetic analysis and mitochondrial functions including mtDNA copy number, ATP and ROS were analyzed. Results: 7 possible pathogenic mutations: MT-TL1 3302A>G, MT-TI 4295A>G, MT-TM 4435A>G, MT-TA 5655T>C, MT-TH 12201T>C, MT-TE 14692A>G and MT-TT 15927G>A were identified in DCM group but absent in controls. These mutations occurred at extremely conserved nucleotides of corresponding tRNAs, and led to the failure in tRNAs metabolism. Moreover, a significant reduction in ATP and mtDNA copy number, whereas a markedly increased in ROS level were observed in polymononuclear leukocytes (PMNs) derived from the DCM patients carrying these mt-tRNA mutations, suggesting that these mutations may cause mitochondrial dysfunction that was responsible for DCM. Conclusions: Our data indicated that mt-tRNA mutations may be the molecular basis for DCM, which shaded novel insight into the pathophysiology of DCM that was manifestated by mitochondrial dysfunction.

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Posttranscriptional modifications in mitochondrial tRNA and its implication in mitochondrial translation and disease

The Journal of Biochemistry ◽

10.1093/jb/mvaa098 ◽

2020 ◽

Vol 168 (5) ◽

pp. 435-444

Author(s):

Tomizawa Kazuhito ◽

Fan-Yan Wei

Keyword(s):

Mitochondrial Diseases ◽

Protein Translation ◽

Fundamental Aspect ◽

Trna Genes ◽

Mitochondrial Translation ◽

Mitochondrial Trna ◽

Genes Encoding ◽

Stability Structure ◽

Life Threatening ◽

Mrna Binding

Abstract A fundamental aspect of mitochondria is that they possess DNA and protein translation machinery. Mitochondrial DNA encodes 22 tRNAs that translate mitochondrial mRNAs to 13 polypeptides of respiratory complexes. Various chemical modifications have been identified in mitochondrial tRNAs via complex enzymatic processes. A growing body of evidence has demonstrated that these modifications are essential for translation by regulating tRNA stability, structure and mRNA binding, and can be dynamically regulated by the metabolic environment. Importantly, the hypomodification of mitochondrial tRNA due to pathogenic mutations in mitochondrial tRNA genes or nuclear genes encoding modifying enzymes can result in life-threatening mitochondrial diseases in humans. Thus, the mitochondrial tRNA modification is a fundamental mechanism underlying the tight regulation of mitochondrial translation and is essential for life. In this review, we focus on recent findings on the physiological roles of 5-taurinomethyl modification (herein referred as taurine modification) in mitochondrial tRNAs. We summarize the findings in human patients and animal models with a deficiency of taurine modifications and provide pathogenic links to mitochondrial diseases. We anticipate that this review will help understand the complexity of mitochondrial biology and disease.

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MELAS-associated m.5541C>T mutation caused instability of mitochondrial tRNATrp and remarkable mitochondrial dysfunction

Journal of Medical Genetics ◽

10.1136/jmedgenet-2020-107323 ◽

2020 ◽

pp. jmedgenet-2020-107323

Author(s):

Kunqian Ji ◽

Yan Lin ◽

Xuebi Xu ◽

Wei Wang ◽

Dongdong Wang ◽

...

Keyword(s):

Mitochondrial Dysfunction ◽

Respiratory Chain ◽

Nuclear Dna ◽

Chain Complex ◽

Trna Genes ◽

Full Potential ◽

Respiratory Chain Complex ◽

Mitochondrial Trna ◽

Taurine Supplementation ◽

Complex Activities

BackgroundMitochondrial encephalomyopathy with lactic acidosis and stroke-like episode (MELAS) is a group of genetic diseases caused by mutations in mitochondrial DNA and nuclear DNA. The causative mutations of MELAS have drawn much attention, among them, mutations in mitochondrial tRNA genes possessing prominent status. However, the detailed molecular pathogenesis of these tRNA gene mutations remains unclear and there are very few effective therapies available to date.MethodsWe performed muscle histochemistry, genetic analysis, molecular dynamic stimulation and measurement of oxygen consumption rate and respiratory chain complex activities to demonstrate the molecular pathomechanisms of m.5541C>T mutation. Moreover, we use cybrid cells to investigate the potential of taurine to rescue mitochondrial dysfunction caused by this mutation.ResultsWe found a pathogenic m.5541C>T mutation in the tRNATrp gene in a large MELAS family. This mutation first affected the maturation and stability of tRNATrp and impaired mitochondrial respiratory chain complex activities, followed by remarkable mitochondrial dysfunction. Surprisingly, we identified that the supplementation of taurine almost completely restored mitochondrial tRNATrp levels and mitochondrial respiration deficiency at the in vitro cell level.ConclusionThe m.5541C>T mutation disturbed the translation machinery of mitochondrial tRNATrp and taurine supplementation may be a potential treatment for patients with m.5541C>T mutation. Further studies are needed to explore the full potential of taurine supplementation as therapy for patients with this mutation.

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Mitochondrial tRNA import – the challenge to understand has just begun

Biological Chemistry ◽

10.1515/bc.2009.101 ◽

2009 ◽

Vol 390 (8) ◽

Cited By ~ 76

Author(s):

Juan D. Alfonzo ◽

Dieter Söll

Keyword(s):

Oxidative Phosphorylation ◽

Mitochondrial Genomes ◽

Trna Genes ◽

Mitochondrial Membranes ◽

Mitochondrial Translation ◽

Mitochondrial Trna ◽

Trna Import ◽

Made In ◽

In Cells

Abstract Mitochondrial translation is important for the synthesis of proteins involved in oxidative phosphorylation, which yields the bulk of the ATP made in cells. During evolution most mitochondria-containing organisms have lost tRNA genes from their mitochondrial genomes. Thus, to support the essential process of nuanced mitochondrial translation, mechanisms to actively transport tRNAs from the cytoplasm across the mitochondrial membranes into the mitochondrion have evolved. Here, we review the currently known tRNA import mechanisms, comment on recent discoveries of various import factors, and suggest a rationale for forces that lie behind the evolution of mitochondrial tRNA import.

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Pathogenic variants in MRPL44 causes infantile cardiomyopathy due to a mitochondrial translation defect

Molecular Genetics and Metabolism ◽

10.1016/j.ymgme.2021.06.001 ◽

2021 ◽

Author(s):

Marisa W. Friederich ◽

Gabrielle C. Geddes ◽

Saskia B. Wortmann ◽

Ann Punnoose ◽

Eric Wartchow ◽

...

Keyword(s):

Mitochondrial Translation ◽

Pathogenic Variants

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Bi-allelic variants in MTMR5/SBF1 cause Charcot-Marie-Tooth type 4B3 featuring mitochondrial dysfunction

BMC Medical Genomics ◽

10.1186/s12920-021-01001-1 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Beatrice Berti ◽

Giovanna Longo ◽

Francesco Mari ◽

Stefano Doccini ◽

Ilaria Piccolo ◽

...

Keyword(s):

Intellectual Disability ◽

Mitochondrial Dysfunction ◽

Early Onset ◽

Integrated Approach ◽

Compound Heterozygous ◽

Charcot Marie Tooth ◽

Charcot Marie Tooth Disease ◽

Pathogenic Variants ◽

First Case ◽

Spine Mri

Abstract Background Charcot-Marie-Tooth disease (CMT) type 4B3 (CMT4B3) is a rare form of genetic neuropathy associated with variants in the MTMR5/SBF1 gene. MTMR5/SBF1 is a pseudophosphatase predicted to regulate endo-lysosomal trafficking in tandem with other MTMRs. Although almost ubiquitously expressed, pathogenic variants primarily impact on the peripheral nervous system, corroborating the involvement of MTMR5/SBF1 and its molecular partners in Schwann cells-mediated myelinization. Case presentation We report a case of severe CMT4B3 characterized by early-onset motor and axonal polyneuropathy in an Italian child in absence of any evidence of brain and spine MRI abnormalities or intellectual disability and with a biochemical profile suggestive of mitochondrial disease. Using an integrated approach combining both NGS gene panels and WES analysis, we identified two novel compound heterozygous missense variants in MTMR5/SBF1 gene, p.R763H (c.2291G > A) and p.G1064E (c.3194G > A). Studies in muscle identified partial defects of oxidative metabolism. Conclusion We describe the first case of an early onset severe polyneuropathy with motor and axonal involvement, due to recessive variants in the MTMR5/SBF1 gene, with no evidence of brain and spine MRI abnormalities, intellectual disability, no clinical and neurophysiological evidences of distal sensory impairment, and rapid neuromuscular deterioration. This report suggests that MTMR5/SBF1 should be considered in cases of infantile-onset CMT with secondary mitochondrial dysfunction.

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Rare Germline Variants in Chordoma-Related Genes and Chordoma Susceptibility

Cancers ◽

10.3390/cancers13112704 ◽

2021 ◽

Vol 13 (11) ◽

pp. 2704

Author(s):

Sally Yepes ◽

Nirav N. Shah ◽

Jiwei Bai ◽

Hela Koka ◽

Chuzhong Li ◽

...

Keyword(s):

Internal Control ◽

Susceptibility Gene ◽

Copy Number Variants ◽

Bone Cancer ◽

Chinese Patients ◽

European Ancestry ◽

Unknown Etiology ◽

Loss Of Function ◽

Single Nucleotide Variants ◽

Pathogenic Variants

Background: Chordoma is a rare bone cancer with an unknown etiology. TBXT is the only chordoma susceptibility gene identified to date; germline single nucleotide variants and copy number variants in TBXT have been associated with chordoma susceptibility in familial and sporadic chordoma. However, the genetic susceptibility of chordoma remains largely unknown. In this study, we investigated rare germline genetic variants in genes involved in TBXT/chordoma-related signaling pathways and other biological processes in chordoma patients from North America and China. Methods: We identified variants that were very rare in general population and internal control datasets and showed evidence for pathogenicity in 265 genes in a whole exome sequencing (WES) dataset of 138 chordoma patients of European ancestry and in a whole genome sequencing (WGS) dataset of 80 Chinese patients with skull base chordoma. Results: Rare and likely pathogenic variants were identified in 32 of 138 European ancestry patients (23%), including genes that are part of notochord development, PI3K/AKT/mTOR, Sonic Hedgehog, SWI/SNF complex and mesoderm development pathways. Rare pathogenic variants in COL2A1, EXT1, PDK1, LRP2, TBXT and TSC2, among others, were also observed in Chinese patients. Conclusion: We identified several rare loss-of-function and predicted deleterious missense variants in germline DNA from patients with chordoma, which may influence chordoma predisposition and reflect a complex susceptibility, warranting further investigation in large studies.

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Three mitochondrial tRNA genes fromArabidopsis thaliana: evidence for the conversion of a tRNAPhegene into a tRNATyrgene

Nucleic Acids Research ◽

10.1093/nar/17.7.2613 ◽

1989 ◽

Vol 17 (7) ◽

pp. 2613-2622 ◽

Cited By ~ 14

Author(s):

Hsu-Ching Chen ◽

Henri Wintz ◽

Jacques-Henry Weil ◽

Datta T.N. Pillay

Keyword(s):

Trna Genes ◽

Mitochondrial Trna ◽

Mitochondrial Trna Genes

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Characterization of mutant mitochondrial plasmids of Neurospora spp. that have incorporated tRNAs by reverse transcription

Molecular and Cellular Biology ◽

10.1128/mcb.9.2.678-691.1989 ◽

1989 ◽

Vol 9 (2) ◽

pp. 678-691

Author(s):

R A Akins ◽

R L Kelley ◽

A M Lambowitz

Keyword(s):

Mitochondrial Dna ◽

Reverse Transcription ◽

Transcription Initiation ◽

Consensus Sequence ◽

Trna Genes ◽

Wild Type ◽

Mitochondrial Trna ◽

Mitochondrial Plasmids ◽

Circular Dnas ◽

Mitochondrial Introns

The Mauriceville and Varkud mitochondrial plasmids of Neurospora spp. are closely related, closed-circular DNAs (3.6 and 3.7 kilobases, respectively) whose nucleotide sequences and genetic organization suggest relationships to mitochondrial introns and retroelements. We have characterized nine suppressive mutants of these plasmids that outcompete mitochondrial DNA and lead to impaired growth. All nine suppressive plasmids contain small insertions, corresponding to or including a mitochondrial tRNA (tRNATrp, tRNAGly, or tRNAVal) or a tRNA-like sequence. The insertions are located at the position corresponding to the 5' end of the major plasmid transcript or 24 nucleotides downstream near a cognate of the sequence at the major 5' RNA end. The structure of the suppressive plasmids suggests that the tRNAs were inserted via an RNA intermediate. The 3' end of the wild-type plasmid transcript can itself be folded into a secondary structure which has tRNA-like characteristics, similar to the tRNA-like structures at the 3' ends of plant viral RNAs. This structure may play a role in replication of the plasmids by reverse transcription. Major transcripts of the suppressive plasmids begin at the 5' end of the inserted mitochondrial tRNA sequence and are present in 25- to 100-fold-higher concentrations than are transcripts of wild-type plasmids. Mapping of 5' RNA ends within the inserted mtDNA sequences identifies a short consensus sequence (PuNPuAG) which is present at the 5' ends of a subset of mitochondrial tRNA genes. This sequence, together with sequences immediately upstream in the plasmids, forms a longer consensus sequence, which is similar to sequences at transcription initiation sites in Neurospora mitochondrial DNA. The suppressive behavior of the plasmids is likely to be directly related to the insertion of tRNAs leading to overproduction of plasmid transcripts.

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