Mitochondrial tRNA mutations associated with deafness

Attardi Institute of Mitochondrial Biomedicine, Wenzhou Medical College, Wenzhou, Zhejiang, China.
Mitochondrion (Impact Factor: 3.25). 04/2012; 12(3):406-13. DOI: 10.1016/j.mito.2012.04.001
Source: PubMed


Mitochondrial tRNA mutations are one of the important causes of both syndromic and non-syndromic deafness. Of those, syndromic deafness-associated tRNA mutations such as tRNA(Leu(UUR)) 3243A>G are often present in heteroplasmy, while non-syndromic deafness-associated tRNA mutations including tRNA(Ser(UCN)) 7445A>G often occur in homplasmy or in high levels of heteroplasmy. These tRNA mutations are the primary mutations leading to hearing loss. However, other tRNA mutations such as tRNA(Thr) 15927G>A and tRNA(Ser(UCN)) 7444G>A may act in synergy with the primary mitochondrial DNA mutations, modulating the phenotypic manifestation of the primary mitochondrial DNA mutations. Theses tRNA mutations cause structural and functional alteration. A failure in tRNA metabolism caused by these tRNA mutations impaired mitochondrial translation and respiration, thereby causing mitochondrial dysfunctions responsible for deafness. These data offer valuable information for the early diagnosis, management and treatment of maternally inherited deafness.

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    • "The non-syndromic deafness-associated tRNA mutations were the tRNASer(UCN) 7445A>G, 7472insC, 7505T>C, 7510T>C and 7511T>C, tRNAHis 12201T>C and tRNAIle 4295A>G mutations (2,9–14). These mutations have structural and functional consequences, including the processing of RNA precursors, nucleotide modification and aminoacylation (6,15). The m.7445A>G mutation altered the processing of the tRNASer(UCN) precursor (16), while the m.4295A>G mutation may affect the nucleotide modification at position 37, 3′ end adjacent to anticodon of the tRNAIle (17). "
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    ABSTRACT: In this report, we investigated the molecular genetic mechanism underlying the deafness-associated mitochondrial tRNAHis 12201T>C mutation. The destabilization of a highly conserved base-pairing (5A-68U) by the m.12201T>C mutation alters structure and function of tRNAHis. Using cybrids constructed by transferring mitochondria from lymphoblastoid cell lines derived from a Chinese family into mtDNA-less (ρo) cells, we showed ∼70% decrease in the steady-state level of tRNAHis in mutant cybrids, compared with control cybrids. The mutation changed the conformation of tRNAHis, as suggested by slower electrophoretic mobility of mutated tRNA with respect to the wild-type molecule. However, ∼60% increase in aminoacylated level of tRNAHis was observed in mutant cells. The failure in tRNAHis metabolism was responsible for the variable reductions in seven mtDNA-encoded polypeptides in mutant cells, ranging from 37 to 81%, with the average of ∼46% reduction, as compared with those of control cells. The impaired mitochondrial translation caused defects in respiratory capacity in mutant cells. Furthermore, marked decreases in the levels of mitochondrial ATP and membrane potential were observed in mutant cells. These mitochondrial dysfunctions caused an increase in the production of reactive oxygen species in the mutant cells. The data provide the evidence for a mitochondrial tRNAHis mutation leading to deafness.
    Full-text · Article · Jun 2014 · Nucleic Acids Research
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    • "The incidence of the mutation in hypoacusic subjects was 2%, a little lower than the one recognised by Berrettini et al(29) in 2008, but similar to the data presented in the studies by Jacobs et al(2) and Lingala et al(30). We could not state if the use of aminoglycosides had any effect on these subjects as they could not recall any exposure to antibiotics in the past; however, one of these patients with severe and progressive HL harboured a novel mutation in position 7471 in tRNASer(UCN), close to position 7472, which has shown to cause both syndromic and non-syndromic deafness (31), suggesting that this variant somehow functions as a modifier, in synergy with the primary mutation, thus modulating its phenotypic manifestations as observed for other tRNA mutations (32). "
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    ABSTRACT: Mutations in mitochondrial DNA (mtDNA) have been shown to be an important cause of sensorineural hearing loss (SNHL). In this study, we performed a clinical and genetic analysis of 169 hearing-impaired patients and some of their relatives suffering from idiopathic SNHL, both familial and sporadic. The analysis of four fragments of their mtDNA identified several polymorphisms, the well known pathogenic mutation, A1555G, and some novel mutations in different genes, implying changes in the aminoacidic sequence. A novel sporadic mutation in 12S rRNA (MT-RNR1), not previously reported in the literature, was found in a case of possible aminoglycoside-induced progressive deafness.
    Full-text · Article · Aug 2013 · International Journal of Molecular Medicine
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    ABSTRACT: Objectives To characterize mitochondrial sequence variants present in a nationwide hereditary deafness DNA repository of samples from deaf subjects and to define the clinical presentation and audiometric characteristics of individuals with a mitochondrial sequence variant.Study DesignRetrospective review of results for select mitochondrial mutations performed on DNA samples from subjects compiled from 1997 to 2009.SettingNational hereditary deafness DNA repository.Subjects and Methods Available samples from subjects in the repository were screened to identify those with mitochondrial sequence variants. Clinical data on the nature of mutation, type and severity of the hearing loss, and sex, age at diagnosis, family history of hearing loss, and ethnicity were analyzed.ResultsEighty-six patients were identified with mitochondrial mutations or 3.5% of the subjects studied. Among those with mitochondrial mutations, 21 (24.4%) had the m.7445A>G substitution, 18 (20.9%) had the m.1555A>G substitution, 18 (20.9%) had the m.961T>G substitution, and 29 (33.7%) had a m.961delT+C(n) complex deletion. The majority of patients had bilateral severe to profound hearing loss. Fifty-three (62%) patients were female, and a family history of hearing loss was documented in 66 (76.7%) patients. The deafness was recognized prior to 3 years of age in 26 patients.Conclusion Mitochondrial deafness in this sample was associated with a variety of genetic mutations and a wide spectrum of clinical presentations. Because of increased aminoglycoside susceptibility associated with some forms of mitochondrial deafness, matrilineal relatives may be at risk in those cases, highlighting the importance of making an accurate diagnosis prior to exposure.
    No preview · Article · Mar 2013 · Otolaryngology Head and Neck Surgery
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