Postlingual Hearing Loss as a Mitochondrial 3243A&gt;G Mutation Phenotype

Iwanicka‐Pronicka, Katarzyna; Pollak, Agnieszka; Skórka, Agata; Lechowicz, Urszula; Pajdowska, Magdalena; Furmanek, Mariusz; Rzeski, Maciej; Korniszewski, L; Skarżyńśki, Henryk; Płoski, Rafał

doi:10.1371/journal.pone.0044054

Cited by 19 publications

(24 citation statements)

References 41 publications

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“…The pattern of audiograms of the m.3243A>G mutation carriers presented a pantonal shape (the flat curve) with slight downward sloping at the higher frequencies, as already described [ 16 ].…”

Section: Resultssupporting

confidence: 69%

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Audio Profiles in Mitochondrial Deafness m.1555A>G and m.3243A>G Show Distinct Differences

et al. 2015

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BackgroundHearing loss is one of the most common symptoms of mitochondrial disorders. However, audiological phenotypes associated with different molecular defects in mtDNA are not yet well characterized.Material/MethodsA large cohort of 1499 nonconsanguineous patients aged 5–40 years with hearing loss of unknown etiology was screened for mutations in mtDNA. For further analysis, patients harboring m.1555A>G and m.3243A>G were selected.Hearing status of the patients was assessed by pure tone audiometry. Patterns of audiograms (hearing threshold levels at each examined frequency) were statistically compared among the carriers of the m.1555A>G and the m.3243A>G mutations.ResultsWe identified 20 patients positive for m.1555A>G mutation and 16 patients positive for m.3243A>G change. The frequency of the above transitions was calculated in our cohort as 1.33% and 1.06%, respectively. Seventeen affected family members carrying the mutations were included into the study.Typical shape of the audiograms in patients with m.1555A>G mutation presented a ski-slope pattern, whereas the audiometric curves among the m.3243A>G individuals had a pantonal shape (a flat curve) with slight downward sloping at the higher frequencies. The differences were statistically significant.The onset of hearing loss was noted earlier among m.1555A>G than m.3243A>G patients (12.5 and 26 years, respectively). Aminoglycoside administration was declared in both groups in 11 and 4 cases respectively, and caused abrupt hearing deterioration in all cases.ConclusionsA pattern of audiogram in patients with mitochondrial deafness may suggest a localization of mtDNA mutation. The pathogenesis of the audiometric differences needs further study.

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Section: Resultssupporting

confidence: 69%

“…All positive samples were directly sequenced to confirm the presence of the mutation. The comparable technology of searching the m.3243A>G mutation was performed and was previously described with details [ 16 ].…”

Section: Methodsmentioning

confidence: 99%

Audio Profiles in Mitochondrial Deafness m.1555A>G and m.3243A>G Show Distinct Differences

et al. 2015

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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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“…Aminoglycoside ototoxicity has been associated with pathogenic variants in MT-RNR1 [34]. Pathogenic variant m.3243A > G in the MT-TL1 gene, which is causative of MELAS, was found in patients with diabetes mellitus and HL or HL exclusively [35]. The data raise questions on mitochondrial variant penetrance, tissue specificity, and heteroplasmy level.…”

Section: Syndromic Hearing Lossmentioning

confidence: 99%

Genetic Basis of Hearing Loss

Pollak¹,

Ołdak²

2018

An Excursus Into Hearing Loss

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Etiology of hearing impairment (HI) is complex and comprises genetic and environmental factors. Currently, the background of genetic hearing impairment is an area of intensive research and we are witnessing fast progress in this field. The story has begun in 1997 when the DFNB1 locus was discovered with GJB2 and GJB6 genes causative for almost 50% of cases of recessive, profound, prelingual hearing loss. Nowadays, we have much more possibilities for dissecting the reason of HI, but proper assessment of clinical symptoms is essential for selecting the most optimal diagnostic pathway. In the first stage, the detailed characteristic of hearing loss including its level established by pure tone audiometry (PTA) or auditory brainstem responses (ABR), age of onset, and other helpful features as progressive or no progressive type should be provided. Subsequently, the presence or absence of accompanying symptoms should be established and followed by a detailed analysis of pedigree. In addition, modern assistive algorithms such as AudioGene, Face2Gene, and POSSUM are also discussed. Taking into account the variety of causative genes and pathogenic variants underling hearing loss, searching for causative genes, after exclusion of the DFNB1 variants, should be performed with multigenic panels based on next-generation sequencing technology.

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Postlingual Hearing Loss as a Mitochondrial 3243A>G Mutation Phenotype

Cited by 19 publications

References 41 publications

Audio Profiles in Mitochondrial Deafness m.1555A>G and m.3243A>G Show Distinct Differences

Audio Profiles in Mitochondrial Deafness m.1555A>G and m.3243A>G Show Distinct Differences

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

Genetic Basis of Hearing Loss

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