title: Mitochondrial m.1584A 12S m62A rRNA methylation in families with m.1555A>G associated hearing loss.
abstract: The mitochondrial DNA mutation m.1555A>G predisposes to hearing loss following aminoglycoside antibiotic exposure in an idiosyncratic dose-independent manner. However, it may also cause maternally inherited hearing loss in the absence of aminoglycoside exposure or any other clinical features (non-syndromic hearing loss). Although m.1555A>G was identified as a cause of deafness more than twenty years ago, the pathogenic mechanism of this mutation of ribosomal RNA remains controversial. Different mechanistic concepts have been proposed. Most recently, evidence from cell lines and animal models suggested that patients with m.1555A>G may have more 12S rRNA N6, N6-dimethyladenosine (m(6) 2A) methylation than controls, so-called 'hypermethylation'. This has been implicated as a pathogenic mechanism of mitochondrial dysfunction but has yet to be validated in patients. 12S m(6) 2A rRNA methylation, by the mitochondrial transcription factor 1 (TFB1M) enzyme, occurs at two successive nucleotides (m.1584A and m.1583A) in close proximity to m.1555A>G. We examined m(6) 2A methylation in 14 patients with m.1555A>G, and controls, and found all detectable 12S rRNA transcripts to be methylated in both groups. Moreover, different RNA samples derived from the same patient (lymphocyte, fibroblast and lymphoblast) revealed that only transformed cells contained some unmethylated 12S rRNA transcripts, with all detectable 12S rRNA transcripts derived from primary samples m(6) 2A-methylated. Our data indicate that TFB1M 12S m(6) 2A rRNA hypermethylation is unlikely to be a pathogenic mechanism and may be an artefact of previous experimental models studied. We propose that RNA methylation studies in experimental models should be validated in primary clinical samples to ensure that they are applicable to the human situation.
authors.affiliation: Genetics and Genomic Medicine, UCL Institute of Child Health, London WC1N 1EH, UK.
authors.forename: Mary
authors.initials: M
authors.lastname: O'Sullivan
authors.affiliation: Genetics and Genomic Medicine, UCL Institute of Child Health, London WC1N 1EH, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Rutland
authors.affiliation: Nuffield Hearing and Speech Centre, Royal National Throat Nose and Ear Hospital, London WC1X 8DA, UK.
authors.forename: Deirdre
authors.initials: D
authors.lastname: Lucas
authors.affiliation: NE Thames Regional Genetics Service.
authors.forename: Emma
authors.initials: E
authors.lastname: Ashton
authors.affiliation: Barnet and Chase Farm Hospitals NHS Trust, Enfield, Middlesex EN2 8JL, UK and.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Hendricks
authors.affiliation: Genetics and Genomic Medicine, UCL Institute of Child Health, London WC1N 1EH, UK, Metabolic Department, Great Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, UK.
authors.forename: Shamima
authors.initials: S
authors.lastname: Rahman
authors.affiliation: Genetics and Genomic Medicine, UCL Institute of Child Health, London WC1N 1EH, UK, Centre for Auditory Research, UCL Ear Institute, London WC1X 8EE, UK maria.bitner@ucl.ac.uk.
authors.forename: Maria
authors.initials: M
authors.lastname: Bitner-Glindzicz
mesh_terms: D000293:Adolescent; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D005190:Family; D005260:Female; D050259:Genes, Mitochondrial; D056726:Genetic Association Studies; D034381:Hearing Loss / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007223:Infant; D008297:Male; D008745:Methylation; D009154:Mutation; D009690:Nucleic Acid Conformation; D010375:Pedigree; D012335:RNA, Ribosomal / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
chemical_list: D012335:RNA, Ribosomal; C075526:RNA, ribosomal, 12S