A six-generation Chinese family in haplogroup B4C1C exhibits high penetrance of 1555A > G-induced hearing Loss

Here, we performed a clinical, molecular, genetic and phylogenic analysis in a six-generation Chinese family.A clinical evaluation revealed that affected individuals without aminoglycoside exposure developed hearing loss extending gradually from 12000 Hz to 8000 Hz and then to 4000 Hz. Using pyrosequencing, we detected an identical homoplasmic 1555A > G mutation in all individuals except one. We did not find any correlation between the mutation load and the severity of hearing loss. T123N coexisted with the 1555A > G mutation in six affected subjects in our pedigree. Analysis of the complete mtDNA genome of this family revealed that this family belonged to haplotype B4C1C and exhibited high penetrance. Upon the inclusion of subjects that had been exposed to aminoglycosides, the penetrance of the hearing loss was 63.6%.; without exposure to aminoglycosides, it was 51.5%. This pedigree and another reported Chinese pedigree share the same haplotype (B4C1C) and lack functionally significant mitochondrial tRNA variants, but nevertheless they exhibit a different penetrance of hearing loss.Our results imply that the factors responsible for the higher penetrance and variable expression of the deafness associated with the 1555A > G mutation in this pedigree may not be mtDNA haplotype/variants, but rather nuclear genes and/or aminoglycosides.A number of mitochondrial mutations have been described to be associated with non-syndromic and syndromic hearing loss. The 1555A > G mutation is the most common mutation attributed to aminoglycoside-induced and non-syndromic deafness. It was first described in a large Arab-Israeli family that exhibited maternally inherited non-syndromic deafness [1].The first family with aminoglycoside-induced hearing impairment was reported by Higashi K [2]. Aminoglycosides exert their antibacterial effect by specifically binding to the bacterial ribosome, thus inhibiting protein synthesis or inducing mistranslation of messenger RNAs [3]. In 1993 Prezan