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Mitochondrial ribosomal RNA gene mutation in a patient with sporadic aminoglycoside ototoxicity
N Fischel-Ghodsian1, T R Prezant, X Bu
1Ahmanson Department of Pediatrics, Steven Spielberg Pediatric Research Center, Los Angeles, CA.
Purpose:
Aminoglycoside-induced deafness has been described in a number of Chinese pedigrees. In nearly all of these families, affected individuals were related through the maternal side. Because mitochondrial DNA is transmitted exclusively through mothers, it had been speculated that a mutation in the mitochondrial DNA might predispose these maternally related family members to aminoglycoside ototoxicity. Recently, we analyzed three such families with multiple cases of ototoxic deafness and identified a pathogenic mutation in the mitochondrial 12S ribosomal RNA gene at nucleotide position 1555. The purpose of the current study is to analyze individuals with no family history of deafness, who had severe hearing loss after aminoglycoside exposure, for presence or absence of this particular mitochondrial DNA mutation.
Materials And Methods:
Blood was obtained from 36 Chinese individuals who became deaf after aminoglycoside exposure and had no family history of deafness. The DNA of these individuals was extracted, amplified by the polymerase chain reaction, and analyzed for the mitochondrial ribosomal RNA gene mutation by allele-specific oligonucleotide hybridization and Southern blot analysis.
Results:
In one of these 36 sporadic cases, we identified the nucleotide 1555 A-->G mutation in the mitochondrial genome.
Conclusion:
This finding implies that a small proportion of individuals at risk for aminoglycoside ototoxicity harbor the specific mitochondrial DNA mutation identified in the familial cases. In these individuals, a genetic susceptibility to the ototoxic effects of aminoglycosides can be diagnosed, and deafness can be prevented in maternal relatives by avoiding the use of these antibiotics.
Insights
A specific mitochondrial DNA mutation (1555 A-->G) in the 12S ribosomal RNA gene can cause aminoglycoside-induced deafness in individuals without a family history. This genetic susceptibility can be diagnosed, allowing for preventative measures in maternal relatives.
Area of Science:
- Genetics
- Otolaryngology
- Molecular Biology
Background:
- Aminoglycoside antibiotics can cause hearing loss (ototoxicity).
- Familial cases of aminoglycoside-induced deafness often show maternal inheritance, suggesting a mitochondrial DNA (mtDNA) role.
- A specific mtDNA mutation (1555 A-->G) in the 12S ribosomal RNA gene was previously identified in familial cases.
Purpose of the Study:
- To investigate the prevalence of the 1555 A-->G mtDNA mutation in individuals with sporadic aminoglycoside-induced deafness.
- To identify genetic susceptibility to ototoxicity in patients without a known family history of hearing loss.
Main Methods:
- Blood samples were collected from 36 Chinese individuals with aminoglycoside-induced deafness and no family history.
- DNA was extracted, amplified using polymerase chain reaction (PCR).
- The 12S ribosomal RNA gene mutation was analyzed using allele-specific oligonucleotide hybridization and Southern blot analysis.
Main Results:
- The pathogenic 1555 A-->G mutation in the mitochondrial genome was identified in one out of 36 sporadic cases.
- This indicates that a subset of individuals with no family history of deafness carry this specific mtDNA mutation.
Conclusions:
- A small proportion of individuals at risk for aminoglycoside ototoxicity harbor the specific mitochondrial DNA mutation.
- Genetic susceptibility to aminoglycoside ototoxicity can be diagnosed in these individuals.
- Preventative strategies, such as avoiding aminoglycoside antibiotics, can protect maternal relatives from developing deafness.