Novel m.4268T>C mutation in the mitochondrial tRNA(Ile) gene is associated with hearing loss in two Chinese families

BACKGROUND: Herein, we report the genetic, clinical, molecular and biochemical features of two Han Chinese pedigrees with suggested maternally transmitted non-syndromic hearing loss. AIM: To investigate the pathophysiology of hearing loss associated with mitochondrial tRNA mutations. METHODS: Sixteen subjects from two Chinese families with hearing loss underwent clinical, genetic, molecular, and biochemical evaluations. Biochemical characterizations included the measurements of tRNA levels using lymphoblastoid cell lines derived from five affected matrilineal relatives of these families and three control subjects. RESULTS: Three of the 16 matrilineal relatives in these families exhibited a variable seriousness and age-at-onset (8 years) of deafness. Analysis of mtDNA mutation identified the novel homoplasmic tRNA(Ile )4268T>C mutation in two families both belonging to haplogroup D4j. The 4268T>C mutation is located in a highly conserved base pairing (6U–67A) of tRNA(Ile). The elimination of 6U–67A base-pairing may change the tRNA(Ile) metabolism. Functional mutation was supported by an approximately 64.6% reduction in the level of tRNA(Ile) observed in the lymphoblastoid cell lines with the 4268T>C mutation, in contrast to the wild-type cell lines. The reduced level of tRNA was below the proposed threshold for normal respiration in lymphoblastoid cells. However, genotyping analysis did not detect any mutations in the prominent deafness-causing gene GJB2 in any members of the family. CONCLUSION: These data show that the novel tRNA(Ile) 4268T>C mutation was involved in maternally transmitted deafness. However, epigenetic, other genetic, or environmental factors may be attributed to the phenotypic variability. These findings will be useful for understanding families with maternally inherited deafness.