Mitochondrial tRNASer(UCN) variants in 2651 Han Chinese subjects with hearing loss

• Eight variants at tRNASer(UCN) gene were identified in a cohort of 2651 Han Chinese hearing-impaired subjects.
• Three known and three putative deafness-associated tRNASer(UCN) mutations accounted for 0.68% cases in this cohort.
• Higher occurrence of haplogroups D4a, M22, and H2 in patients carrying the tRNASer(UCN) mutations than those in controls.
• The tRNASer(UCN) gene is the hot spot for mutations associated with hearing loss.

Mutations in the mitochondrial DNA have been associated with hearing loss. However, the prevalence and spectrum of mitochondrial tRNA mutations in hearing-impaired subjects are poorly understood. In this report, we have investigated the prevalence and spectrum of mitochondrial tRNASer(UCN) mutations in a large cohort of 2651 Han Chinese subjects with hearing loss. The clinical evaluation showed that 744 subjects (432 males and 312 females) had a history of exposure to aminoglycosides and other probands exhibited nonsyndromic hearing loss. Mutational analysis of tRNASer(UCN) gene identified 9 (8 known and 1 novel) variants. The prevalence of the known deafness-associated 7511T>C, 7505T>C and 7445A>C mutations was 0.04%, 0.04% and 0.04%, respectively. Other variants were evaluated by the evolutionary conservation, allelic frequency of Chinese controls, potential structural and functional alterations and pedigree analysis. Three variants were polymorphisms, while the 7444G>A, 7471DelG and 7496A>G variants were putative deafness-associated mutations. These putative deafness-associated variants accounted for 0.68% cases of hearing-impaired subjects in this cohort. The low penetrance of hearing loss in pedigrees carrying one of these putative deafness-associated mutations indicated that the mutation(s) is necessary but itself insufficient to produce a clinical phenotype. Other genetic or environmental factor(s) may influence the phenotypic manifestation of these tRNASer(UCN) mutations. Moreover, mtDNAs in 20 probands carrying one of the putative deafness-associated mutations were widely dispersed among 8 Eastern Asian haplogroups. In particular, the occurrences of haplogroups D4a, M22, and H2 in patients carrying the deafness-associated variants were higher than those in Chinese controls. These data further support that the mitochondrial tRNASer(UCN) gene is the hot spot for mutations associated with hearing loss. Thus, our findings may provide valuable information for the further understanding of pathophysiology and management of hearing loss.