Maternally inherited hearing loss is associated with the novel mitochondrial tRNASer(UCN) 7505T>C mutation in a Han Chinese family

Abstract: Mutations in mitochondrial DNA (mtDNA) have been found to be one of the most important causes of sensorineural hearing loss. We report here a clinical, genetic, molecular and biochemical characterization of a Han Chinese pedigree with maternally transmitted nonsyndromic hearing impairment. Seven of nine matrilineal relatives exhibited a variable severity and age-at-onset (8years old) of hearing loss. Mutational analysis of mtDNA identified the novel homoplasmic tRNASer(UCN) 7505T>C mutation and other 37 variants belonging to haplogroup F1. The 7505T>C mutation, which is absent in 449 Chinese controls, is located at a highly conserved base-pairing (10A–20U) of tRNASer(UCN). The abolishment of 10A–20U base-pairing likely alters the tRNASer(UCN) metabolism. Functional significant of this mutation was supported by ∼65% reductions in the level of tRNASer(UCN) observed in the lymphoblastoid cell lines carrying the 7505T>C mutation, compared with the wild-type cell lines. This reduced tRNA level is below the proposed threshold to support a normal respiration in lymphoblastoid cells. Furthermore, the highly conserved tRNAAla 5587T>C and Cytb C93Y variants may have a modifying role of deafness expression associated with the 7505T>C mutation. However, genotyping analysis of nuclear modifier gene TRMU and the prominent deafness-cause gene GJB2 failed to detect any mutations in the member of this family. These data strongly indicate that the novel tRNASer(UCN) 7505T>C mutation is involved in maternally transmitted hearing loss. However, other genetic, epigenetic or environmental factors may contribute to the phenotypic variability of this family. Our findings will be helpful for counseling families of maternally inherited hearing loss. [Copyright &y& Elsevier]