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
tRNA(His).
tRNA northern analysis revealed that the T12201C mutation caused an ∼75% reduction in the steady-state level of
tRNA(His). 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
tRNA(His) 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.