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 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.