Identification of a mitochondrial 12S rRNA A1555G mutation causing aminoglycoside-induced deafness in a large Thai family

PCR–Sanger sequencing of III-5 revealed that the patient had a homoplasmic A>G mutation at nucleotide position 1555 of the MT-RNR1 (Figure 2). PCR–restriction fragment length polymorphism (RFLP) showed that the other three affected members, III-1, III-3, and III-4, also harbored the homoplasmic A1555G mutation (Figure 3), while the unaffected IV-1 had only the wild-type nucleotide.

Figure 2

Figure 3

In our study, we first analyzed the A1555G mutation in the MT-RNR1 gene by PCR–Sanger sequencing in our proband. Then we performed RFLP analysis to determine the presence of this mutation in other family members. The mutation analyses showed that this family had the mitochondrial genetic susceptibility for aminoglycoside-induced deafness.

With a prevalence of almost 1 in 400 individuals in the British population [9], the A1555G mitochondrial variant could be considered common in some ethnic groups. As long as people with this genetic susceptibility are not given aminoglycosides, they could remain healthy with normal hearing throughout their entire life [9]. Nonetheless, there was an observation that the A1555G mutation could cause hearing loss even without exposure to aminoglycosides. The hearing loss in these cases tends to be later onset and less severe compared with those exposed to aminoglycosides [10]. By contrast, there has been a recent report of a child with a A1555G mutation who has normal hearing despite repeated exposure to aminoglycosides [11]. Factors affecting penetrance of this genetic susceptibility require further investigations.

Aminoglycosides produce their antibacterial effects by binding to the 30S ribosomal subunit of bacterial ribosomes, which alters their conformation. This leads to codon misreading of RNA, induces errors in protein synthesis, and results in bacterial death [12]. Because structural differences lower the drug’s affinity for eukaryotic ribosomes, aminoglycosides do not normally bind to human ribosomes, and therefore are generally safe for human use [4]. However, the mutation at position 1555 from adenine to guanine in human MT-RNR1 causes a structural rearrangement, which increases structural similarity of human mitochondrial rRNA to bacterial rRNA, promoting aminoglycoside binding. This can lead to a misreading in mitochondrial protein synthesis, which decreases mitochondrial ATP synthesis, compromises ion pump activity, and progressively decreases endocochlear potential, ultimately resulting in hearing loss [13].

Our present finding demonstrated that the A1555G mitochondrial mutation causing aminoglycoside-induced deafness, reported in several families worldwide, is also present in the Thai population. This genetic susceptibility is located within human mitochondrial DNA; therefore it is maternally inherited transferring from mothers to their children. Therefore, it is important that medical practitioners in Thailand be aware of this mitochondrial DNA mutation. This mutation should be considered before prescribing aminoglycosides, especially when there is deafness reported in a patient’s family history. Patients who have this mutation should be prescribed with an alternative antibiotic to avoid this preventable deafness.