Mitochondrial tRNASer(UCN) variants in 2651 Han Chinese subjects with hearing loss

Tang, Xiaowen; Zheng, Jing; Ying, Zhengbiao; Cai, Zhaoyang; Gao, Yinglong; He, Zheyun; Yu, Han; Yao, Juan; Yang, Yaling; Wang, Hui; Chen, Ye; Guan, Min‐Xin

doi:10.1016/j.mito.2015.05.001

Cited by 20 publications

(19 citation statements)

References 47 publications

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“…The pedigree of the Chinese family with maternally inherited deafness was previously described (19,26). Six of 12 matrilineal relatives suffered from the variable degree of hearing impairment (two with mild hearing loss, two with moderate hearing loss and two with profound hearing loss).…”

Section: Resultsmentioning

confidence: 99%

“…As the part of a genetic screening program for deafness in a cohort of 2651 Han Chinese affected subjects, we identified the novel m.7551A > G mutation in the mt–tRNA Asp gene in one Han Chinese pedigrees with maternal transmission of nonsyndromic deafness (19,26). As shown in Figure 1, the m.7551A > G mutation is localized at a highly conserved nucleotide (A37), adjacent (3′) to the anticodon of mt–tRNA Asp (22,23).…”

Section: Introductionmentioning

confidence: 99%

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A deafness-associated tRNA^Aspmutation alters the m¹G37 modification, aminoacylation and stability of tRNA^Aspand mitochondrial function

et al. 2016

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In this report, we investigated the pathogenic mechanism underlying the deafness-associated mitochondrial(mt) tRNAAsp 7551A > G mutation. The m.7551A > G mutation is localized at a highly conserved nucleotide(A37), adjacent (3′) to the anticodon, which is important for the fidelity of codon recognition and stabilization in functional tRNAs. It was anticipated that the m.7551A > G mutation altered the structure and function of mt-tRNAAsp. The primer extension assay demonstrated that the m.7551A > G mutation created the m1G37 modification of mt-tRNAAsp. Using cybrid cell lines generated by transferring mitochondria from lymphoblastoid cell lines derived from a Chinese family into mitochondrial DNA(mtDNA)-less (ρo) cells, we demonstrated the significant decreases in the efficiency of aminoacylation and steady-state level of mt-tRNAAsp in mutant cybrids, compared with control cybrids. A failure in metabolism of mt-tRNAAsp caused the variable reductions in mtDNA-encoded polypeptides in mutant cybrids. Impaired mitochondrial translation led to the respiratory phenotype in mutant cybrids. The respiratory deficiency lowed mitochondrial adenosine triphosphate production and increased the production of oxidative reactive species in mutant cybrids. Our data demonstrated that mitochondrial dysfunctions caused by the m.7551A > G mutation are associated with deafness. Our findings may provide new insights into the pathophysiology of maternally transmitted deafness that was manifested by altered nucleotide modification of mitochondrial tRNA.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A deafness-associated tRNA^Aspmutation alters the m¹G37 modification, aminoacylation and stability of tRNA^Aspand mitochondrial function

et al. 2016

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“…Subjects-A total of 2651 Chinese hearing-impaired probands were recruited from the Otology Clinics, Wenzhou Medical University, China, as detailed previously (25,26). This study was in compliance with the Declaration of Helsinki.…”

Section: Methodsmentioning

confidence: 99%

“…As part of a genetic screening program for deafness in a cohort of 2651 Han Chinese hearing-impaired subjects (25,26), we identified the U-to-C transition at position 14692 (m.14692A3 G) in the tRNA Glu gene in three genetically unrelated probands whose families exhibited the maternal transmission of deafness and diabetes. As shown in Fig.…”

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confidence: 99%

A Deafness- and Diabetes-associated tRNA Mutation Causes Deficient Pseudouridinylation at Position 55 in tRNAGlu and Mitochondrial Dysfunction

Wang

Líu

Zheng

et al. 2016

Journal of Biological Chemistry

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Several mitochondrial tRNA mutations have been associated with maternally inherited diabetes and deafness. However, the pathophysiology of these tRNA mutations remains poorly understood. In this report, we identified the novel homoplasmic 14692A→G mutation in the mitochondrial tRNA gene among three Han Chinese families with maternally inherited diabetes and deafness. The m.14692A→G mutation affected a highly conserved uridine at position 55 of the TΨC loop of tRNA The uridine is modified to pseudouridine (Ψ55), which plays an important role in the structure and function of this tRNA. Using lymphoblastoid cell lines derived from a Chinese family, we demonstrated that the m.14692A→G mutation caused loss of Ψ55 modification and increased angiogenin-mediated endonucleolytic cleavage in mutant tRNA The destabilization of base-pairing (18A-Ψ55) caused by the m.14692A→G mutation perturbed the conformation and stability of tRNA An approximately 65% decrease in the steady-state level of tRNA was observed in mutant cells compared with control cells. A failure in tRNA metabolism impaired mitochondrial translation, especially for polypeptides with a high proportion of glutamic acid codons such as ND1, ND6, and CO2 in mutant cells. An impairment of mitochondrial translation caused defective respiratory capacity, especially reducing the activities of complexes I and IV. Furthermore, marked decreases in the levels of mitochondrial ATP and membrane potential were observed in mutant cells. These mitochondrial dysfunctions caused an increasing production of reactive oxygen species in the mutant cells. Our findings may provide new insights into the pathophysiology of maternally inherited diabetes and deafness, which is primarily manifested by the deficient nucleotide modification of mitochondrial tRNA.

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“…Mutations in LARS2, NARS2, and KARS encoding mitochondrial leucyl-tRNA synthetase, asparaginyl-tRNA synthetase, and lysyl-tRNA synthetase have been associated with deafness, respectively (8 -10). The mitochondrial tRNA genes are the hot spots for deafness-associ-ated mutations, including the tRNA Leu(UUR) 3243A3 G, tRNA Ser(UCN) 7445A3 G, 7511T3 C, tRNA His 12201T3 C, tRNA Asp 7551A3 G, and tRNA Glu 14692A3 G mutations (11)(12)(13)(14)(15)(16)(17). The m.1555A3 G and m.1494C3 T mutations in the 12S rRNA gene have been associated with both aminoglycoside-induced and nonsyndromic deafness in many families worldwide (3, 4, 18 -20).…”

Section: Edited By Linda Spremullimentioning

confidence: 99%

Biochemical Evidence for a Nuclear Modifier Allele (A10S) in TRMU (Methylaminomethyl-2-thiouridylate-methyltransferase) Related to Mitochondrial tRNA Modification in the Phenotypic Manifestation of Deafness-associated 12S rRNA Mutation

Meng

Cang

Peng

et al. 2017

Journal of Biological Chemistry

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Nuclear modifier gene(s) was proposed to modulate the phenotypic expression of mitochondrial DNA mutation(s). Our previous investigations revealed that a nuclear modifier allele (A10S) in TRMU (methylaminomethyl-2-thiouridylate-methyltransferase) related to tRNA modification interacts with 12S rRNA 1555A→G mutation to cause deafness. The A10S mutation resided at a highly conserved residue of the N-terminal sequence. It was hypothesized that the A10S mutation altered the structure and function of TRMU, thereby causing mitochondrial dysfunction. Using molecular dynamics simulations, we showed that the A10S mutation introduced the Ser dynamic electrostatic interaction with the Lys residue of helix 4 within the catalytic domain of TRMU. The Western blotting analysis displayed the reduced levels of TRMU in mutant cells carrying the A10S mutation. The thermal shift assay revealed the value of mutant TRMU protein, lower than that of the wild-type counterpart. The A10S mutation caused marked decreases in 2-thiouridine modification of U34 of tRNA, tRNA and tRNA However, the A10S mutation mildly increased the aminoacylated efficiency of tRNAs. The altered 2-thiouridine modification worsened the impairment of mitochondrial translation associated with the m.1555A→G mutation. The defective translation resulted in the reduced activities of mitochondrial respiration chains. The respiratory deficiency caused the reduction of mitochondrial ATP production and elevated the production of reactive oxidative species. As a result, mutated TRMU worsened mitochondrial dysfunctions associated with m.1555A→G mutation, exceeding the threshold for expressing a deafness phenotype. Our findings provided new insights into the pathophysiology of maternally inherited deafness that was manifested by interaction between mtDNA mutation and nuclear modifier gene.

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Mitochondrial tRNASer(UCN) variants in 2651 Han Chinese subjects with hearing loss

Cited by 20 publications

References 47 publications

A deafness-associated tRNA^Aspmutation alters the m¹G37 modification, aminoacylation and stability of tRNA^Aspand mitochondrial function

A deafness-associated tRNA^Aspmutation alters the m¹G37 modification, aminoacylation and stability of tRNA^Aspand mitochondrial function

A Deafness- and Diabetes-associated tRNA Mutation Causes Deficient Pseudouridinylation at Position 55 in tRNAGlu and Mitochondrial Dysfunction

Biochemical Evidence for a Nuclear Modifier Allele (A10S) in TRMU (Methylaminomethyl-2-thiouridylate-methyltransferase) Related to Mitochondrial tRNA Modification in the Phenotypic Manifestation of Deafness-associated 12S rRNA Mutation

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Mitochondrial tRNASer(UCN) variants in 2651 Han Chinese subjects with hearing loss

Cited by 20 publications

References 47 publications

A deafness-associated tRNAAspmutation alters the m1G37 modification, aminoacylation and stability of tRNAAspand mitochondrial function

A deafness-associated tRNAAspmutation alters the m1G37 modification, aminoacylation and stability of tRNAAspand mitochondrial function

A Deafness- and Diabetes-associated tRNA Mutation Causes Deficient Pseudouridinylation at Position 55 in tRNAGlu and Mitochondrial Dysfunction

Biochemical Evidence for a Nuclear Modifier Allele (A10S) in TRMU (Methylaminomethyl-2-thiouridylate-methyltransferase) Related to Mitochondrial tRNA Modification in the Phenotypic Manifestation of Deafness-associated 12S rRNA Mutation

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A deafness-associated tRNA^Aspmutation alters the m¹G37 modification, aminoacylation and stability of tRNA^Aspand mitochondrial function

A deafness-associated tRNA^Aspmutation alters the m¹G37 modification, aminoacylation and stability of tRNA^Aspand mitochondrial function