Maternally Inherited Aminoglycoside-Induced and Nonsyndromic Deafness Is Associated with the Novel C1494T Mutation in the Mitochondrial 12S rRNA Gene in a Large Chinese Family

Abstract

We report here the characterization of a large Chinese family with maternally transmitted aminoglycoside-induced and nonsyndromic deafness. In the absence of aminoglycosides, some matrilineal relatives in this family exhibited late-onset/progressive deafness, with a wide range of severity and age at onset. Notably, the average age at onset of deafness has changed from 55 years (generation II) to 10 years (generation IV). Clinical data reveal that the administration of aminoglycosides can induce or worsen deafness in matrilineal relatives. The age at the time of drug administration appears to be correlated with the severity of hearing loss experienced by affected individuals. Sequence analysis of mitochondrial DNA in this pedigree identified a homoplasmic C-to-T transition at position 1494 (C1494T) in the 12S rRNA gene. The C1494T mutation is expected to form a novel U1494-1555A base pair, which is in the same position as the C1494-1555G pair created by the deafness-associated A1555G mutation, at the highly conserved A site of 12S rRNA. Exposure to a high concentration of paromomycin or neomycin caused a variable but significant average increase in doubling time in lymphoblastoid cell lines derived from four symptomatic and two asymptomatic individuals in this family carrying the C1494T mutation when compared to four control cell lines. Furthermore, a significant decrease in the rate of total oxygen consumption was observed in the mutant cell lines. Thus, our data strongly support the idea that the A site of mitochondrial 12S rRNA is the primary target for aminoglycoside-induced deafness. These results also strongly suggest that the nuclear background plays a role in the aminoglycoside ototoxicity and in the development of the deafness phenotype associated with the C1494T mutation in the mitochondrial 12S rRNA gene.

Assessment of Nutrient Supplement to Reduce Gentamicin-Induced Ototoxicity

“…Variable estimates on ototoxicity may also be related to patient history. For example, specific mitochondrial defects that are more prevalent in some Asian populations produce extreme sensitivity to aminoglycoside ototoxicity (Usami et al 1998;Zhao et al 2004; for review see Bindu and Reddy 2008). Additionally, previous aminoglycoside treatment has been suggested to effect risk of ototoxicity from subsequent administration based on cumulative drug dose (Chen et al 2013).…”

The 12S rRNA A1555G mutation in the mitochondrial haplogroup D5a is responsible for maternally inherited hypertension and hearing loss in two Chinese pedigrees

“…[10][11][12] The other non-syndromic deafness-associated mtDNA mutations are the 12S rRNA C1494T mutation, the 7472insC, T7505C and T7511C mutations in the tRNA Ser(UCN) gene ,and the T12201C mutation in the tRNA His gene. [13][14][15][16][17] The 12S rRNA mutations impaired mitochondrial translation, leading to deficient respiration. 13,18,19 Mild mitochondrial dysfunctions were observed in cells carrying these mtDNA mutations.…”

“…[13][14][15][16][17] The 12S rRNA mutations impaired mitochondrial translation, leading to deficient respiration. 13,18,19 Mild mitochondrial dysfunctions were observed in cells carrying these mtDNA mutations. 13,18,19 Therefore, these mtDNA mutations are necessary but insufficient to produce a clinical phenotype.…”

A novel method of detecting mitochondrial m.1494C>T and m.1555A>G mutations in a single PCR reaction using base-quenched probe

“…It has been reported that several mutations in the mitochondrial DNA (mtDNA), including m.1555A>G [3], m.1494C>T [4], m.1095T>C [5], m.837A>G [6], and m.1291T>C [7] may possibly associate with the sensorineural hearing loss, and mutations of m.1555A>G and m.1494C>T at the highly conserved decoding site of 12S rRNA are well documented being associated to either aminoglycoside antibiotics-induced or non-syndromic hearing loss in families with different ethnic backgrounds [3,4,8,9].…”

“…m.1555A>G mutation in a highly conserved decoding site of the 12S rRNA could associate with both aminoglycoside-induced and non-syndromic hearing loss in families with different ethnic backgrounds, [3,9,17], and the m.1494C>T mutation is also structurally equivalent to the m.1555A>G mutation in the 12SrRNA gene [4,10,11,18].…”