An MRPS12 mutation modifies aminoglycoside sensitivity caused by 12S rRNA mutations

Area of Science:

• Genetics
• Evolutionary Biology
• Mitochondrial Biology

Background:

• Incomplete penetrance of pathogenic mitochondrial DNA mutations necessitates identifying modifying factors.
• Conventional genetic approaches are often insufficient for multifactorial diseases.

Purpose of the Study:

• To uncover modifying factors for the m.1494C>T mitochondrial DNA mutation linked to aminoglycoside-induced and non-syndromic hearing loss using an evolutionary strategy.
• Investigate the role of compensatory mutations in mitigating the pathogenicity of mitochondrial DNA mutations.

Main Methods:

• Examined mammalian species with the m.1494C>T mutation to identify compensated pathogenic deviations.
• Analyzed primary fibroblasts from Cercopithecidae species to assess aminoglycoside effects.
• Expressed a variant mitochondrial ribosomal protein in a human m.1494T cell line.

Main Results:

• Cercopithecidae primates harbor the m.1494T allele without auditory impairment, unlike humans.
• Aminoglycosides did not affect cell growth or mitochondrial function in Cercopithecidae fibroblasts.
• A fixed mutation in mitochondrial ribosomal protein S12 in Cercopithecidae suppressed aminoglycoside susceptibility in a human cell line.

Conclusions:

• A mitochondrial ribosomal protein variant acts as a modifier, suppressing the pathogenic effects of the m.1494C>T mitochondrial DNA mutation.
• This finding suggests potential explanations for incomplete penetrance in mitochondrial inherited hearing loss and offers therapeutic avenues.