Several homoplasmic pathologic mutations in mitochondrial DNA, such as those causing Leber hereditary optic neuropathy or non-syndromic hearing loss, show incomplete penetrance. Therefore, other elements must modify their pathogenicity. Discovery of these modifying factors is not an easy task because in multifactorial diseases conventional genetic approaches may not always be informative.

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Here, we have taken an evolutionary approach to unmask putative modifying factors for a particular homoplasmic pathologic mutation causing aminoglycoside-induced and non-syndromic hearing loss, the m.1494C>T transition in the mitochondrial DNA. The mutation is located in the decoding site of the mitochondrial ribosomal RNA. We first looked at mammalian species that had fixed the human pathologic mutation. These mutations are called compensated pathogenic deviations because an organism carrying one must also have another that suppresses the deleterious effect of the first. We found that species from the primate family Cercopithecidae (old world monkeys) harbor the m.1494T allele even if their auditory function is normal. In humans the m.1494T allele increases the susceptibility to aminoglycosides. However, in primary fibroblasts from a Cercopithecidae species, aminoglycosides do not impair cell growth, respiratory complex IV activity and quantity or the mitochondrial protein synthesis.

Interestingly, this species also carries a fixed mutation in the mitochondrial ribosomal protein S12. We show that the expression of this variant in a human m.1494T cell line reduces its susceptibility to aminoglycosides. Because several mutations in this human protein have been described, they may possibly explain the absence of pathologic phenotype in some pedigree members with the most frequent pathologic mutations in mitochondrial ribosomal RNA.

Introduction Human cells contain many mitochondria and each mitochondrion several mitochondrial DNA (mtDNA) molecules. The absence of mtDNA genetic variation in a person is named homoplasmy. However, homoplasmic mutations can be found in a particular individual when his/her mtDNA is different from a reference sequence, the revised Cambridge Reference Sequence (rCRS). If these mutations do not have phenotypic effect, they can survive in the populations for long periods of time. On the contrary, if mutations have very dramatic functional effects, they will be very quickly removed from the populations. In between, there are several pathologic mtDNA mutations with moderate phenotypic effects.

These are the etiologic factors for some of the most frequent mtDNA diseases, such as the Leber hereditary optic neuropathy (LHON) and the non-syndromic hearing loss (NSHL) (Fischel-Ghodsian,; Carelli et al., ). A common feature for these homoplasmic mutations with moderate functional effect is their tissue-specificity. For example, despite being present in every mtDNA molecule of each cell, LHON and NSHL mutations mainly affect retinal ganglion and cochlear cells, respectively. This fact suggests that tissue-specific factors, including the specific set of expressed proteins, are required for the manifestation of the pathologic phenotype (Hamalainen et al., ). Carlos Azevedo Biologia Celular Molecular Pdf Reader.

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It is also frequently found that maternal relatives of patients carrying homoplasmic mutations are asymptomatic. This fact, again, suggests that other environmental and genetic factors are necessary for the phenotypic expression (Fischel-Ghodsian,; Carelli et al., ). The m.1494C>T mutation in the 12S rRNA gene ( MT-RNR1) was found in several NSHL patients from a Chinese family. The oxygen consumption was lower in lymphoblastoid cell lines from homoplasmic mutant individuals (Zhao et al., ).