Maternally transmitted late-onset non-syndromic deafness is associated with the novel heteroplasmic T12201C mutation in the mitochondrial tRNAHis gene
- 19 September 2011
- journal article
- research article
- Published by BMJ in Journal of Medical Genetics
- Vol. 48 (10), 682-690
- https://doi.org/10.1136/jmedgenet-2011-100219
Abstract
The authors report here the clinical, genetic, molecular and biochemical characterisation of a large five-generation Han Chinese pedigree with maternally transmitted non-syndromic hearing loss. 17 of 35 matrilineal relatives exhibited variable severity and age at onset of sensorineural hearing loss. The average age at onset of hearing loss in matrilineal relatives of this family is 29 years, while matrilineal relatives among families carrying other mitochondrial DNA mutations developed hearing loss with congenital conditions or early age at onset. Molecular analysis of their mitochondrial genome identified the novel heteroplasmic T12201C mutation in the transfer RNA (tRNA)His gene. The levels of T12201C mutation in matrilineal relatives of this family correlated with the severity and age at onset of non-syndromic hearing loss. By contrast, other heteroplasmic mitochondrial DNA mutations often cause syndromic hearing loss. The T12201C mutation destabilises a highly conservative base-pairing (5A-68U) on the acceptor stem of tRNAHis. tRNA northern analysis revealed that the T12201C mutation caused an ∼75% reduction in the steady-state level of tRNAHis. An in vivo protein labeling analysis showed an ∼47% reduction in the rate of mitochondrial translation in cells carrying the T12201C mutation. Impaired mitochondrial translation is apparently a primary contributor to the marked reduction in the rate of overall respiratory capacity, malate/glutamate-promoted respiration, succinate/glycerol-3-phosphate-promoted respiration or N,N,Ń,Ń-tetramethyl-p-phenylenediamine/ascorbate-promoted respiration. These data provide the first direct evidence that mitochondrial dysfunctions caused by the heteroplasmic tRNAHis mutation lead to late-onset non-syndromic deafness. Thus, the authors' findings provide new insights into the understanding of pathophysiology and valuable information on the management and treatment of maternally inherited hearing loss.Keywords
This publication has 45 references indexed in Scilit:
- Mitochondrial 12S rRNA variants in 1642 Han Chinese pediatric subjects with aminoglycoside-induced and nonsyndromic hearing lossMitochondrion, 2010
- Maternally inherited hearing loss is associated with the novel mitochondrial tRNASer(UCN) 7505T>C mutation in a Han Chinese familyMolecular Genetics and Metabolism, 2010
- Human Mitochondrial Leucyl-tRNA Synthetase Corrects Mitochondrial Dysfunctions Due to the tRNALeu(UUR) A3243G Mutation, Associated with Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Symptoms and DiabetesMolecular and Cellular Biology, 2010
- Mitochondrial haplotypes may modulate the phenotypic manifestation of the deafness-associated 12S rRNA 1555A>G mutationMitochondrion, 2010
- An enhanced MITOMAP with a global mtDNA mutational phylogenyNucleic Acids Research, 2006
- Mutation in TRMU Related to Transfer RNA Modification Modulates the Phenotypic Expression of the Deafness-Associated Mitochondrial 12S Ribosomal RNA MutationsAmerican Journal of Human Genetics, 2006
- Tissue-Specific Differences in Human Transfer RNA ExpressionPLoS Genetics, 2006
- Mitochondrial DNA mutations in human diseaseNature Reviews Genetics, 2005
- The prevalence of connexin 26 ( GJB2 ) mutations in the Chinese populationHuman Genetics, 2002
- Maternally transmitted diabetes and deafness associated with a 10.4 kb mitochondrial DNA deletionNature Genetics, 1992