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.
- Cardiovascular medicine
- gene therapy
- molecular genetics
- metabolic disorders
- cell biology
- cardiovascular medicine
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XY and XW equally contributed to this work.
Funding This work was supported by Public Health Service grants RO1DC05230 and RO1DC07696 from the National Institute on Deafness and Other Communication Disorders; National Basic Research Priorities Program of China grant 2004CCA02200 and Ministry of Science and Technology of Zhejiang Province grant 2007G50G2090026 to MXG; National Basic Research Program of China (973 Program) grants 2011CB504506, 2010CB945503 and 2006CB943701; and National Natural Science Foundation of China grants 30772399, 81070793 and 30901668 to H Li, grant 30971600 to R Li and grant 81070794 to Y Zhu.
Competing interests None.
Patient consent Obtained.
Ethics approval IRB from Cincinnati Children's Hospital Medical Center.
Provenance and peer review Not commissioned; externally peer reviewed.