An MRPS12 mutation modifies aminoglycoside sensitivity caused by 12S rRNA mutations
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 becaus...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2015-01-01
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| Series: | Frontiers in Genetics |
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| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fgene.2014.00469/full |
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| author | Sonia eEmperador Sonia eEmperador Sonia eEmperador David ePacheu-Grau M. Pilar eBayona-Bafaluy Nuria eGarrido-Pérez Antonio eMartín-Navarro Manuel José López-Pérez Manuel José López-Pérez Manuel José López-Pérez Julio eMontoya Julio eMontoya Julio eMontoya Eduardo eRuiz-Pesini Eduardo eRuiz-Pesini Eduardo eRuiz-Pesini Eduardo eRuiz-Pesini |
| author_facet | Sonia eEmperador Sonia eEmperador Sonia eEmperador David ePacheu-Grau M. Pilar eBayona-Bafaluy Nuria eGarrido-Pérez Antonio eMartín-Navarro Manuel José López-Pérez Manuel José López-Pérez Manuel José López-Pérez Julio eMontoya Julio eMontoya Julio eMontoya Eduardo eRuiz-Pesini Eduardo eRuiz-Pesini Eduardo eRuiz-Pesini Eduardo eRuiz-Pesini |
| author_sort | Sonia eEmperador |
| collection | DOAJ |
| description | 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.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, these species also carry 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. |
| first_indexed | 2024-04-14T05:59:19Z |
| format | Article |
| id | doaj.art-d231ab10053b4e4abdbb6963a77628df |
| institution | Directory Open Access Journal |
| issn | 1664-8021 |
| language | English |
| last_indexed | 2024-04-14T05:59:19Z |
| publishDate | 2015-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Genetics |
| spelling | doaj.art-d231ab10053b4e4abdbb6963a77628df2022-12-22T02:08:50ZengFrontiers Media S.A.Frontiers in Genetics1664-80212015-01-01510.3389/fgene.2014.00469124045An MRPS12 mutation modifies aminoglycoside sensitivity caused by 12S rRNA mutationsSonia eEmperador0Sonia eEmperador1Sonia eEmperador2David ePacheu-Grau3M. Pilar eBayona-Bafaluy4Nuria eGarrido-Pérez5Antonio eMartín-Navarro6Manuel José López-Pérez7Manuel José López-Pérez8Manuel José López-Pérez9Julio eMontoya10Julio eMontoya11Julio eMontoya12Eduardo eRuiz-Pesini13Eduardo eRuiz-Pesini14Eduardo eRuiz-Pesini15Eduardo eRuiz-Pesini16Universidad de ZargozaInstituto de Investigación SanitariaCIBERERUniversidad de ZargozaUniversidad de ZargozaUniversidad de ZargozaUniversidad de ZargozaUniversidad de ZargozaInstituto de Investigación SanitariaCIBERERUniversidad de ZargozaInstituto de Investigación SanitariaCIBERERUniversidad de ZargozaInstituto de Investigación SanitariaCIBERERARAIDSeveral 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.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, these species also carry 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.http://journal.frontiersin.org/Journal/10.3389/fgene.2014.00469/fullaminoglycosideEvolutionary approachesCompensatory mutationIncomplete penetrancepathologic mutationMitochondrial ribosomal RNA |
| spellingShingle | Sonia eEmperador Sonia eEmperador Sonia eEmperador David ePacheu-Grau M. Pilar eBayona-Bafaluy Nuria eGarrido-Pérez Antonio eMartín-Navarro Manuel José López-Pérez Manuel José López-Pérez Manuel José López-Pérez Julio eMontoya Julio eMontoya Julio eMontoya Eduardo eRuiz-Pesini Eduardo eRuiz-Pesini Eduardo eRuiz-Pesini Eduardo eRuiz-Pesini An MRPS12 mutation modifies aminoglycoside sensitivity caused by 12S rRNA mutations Frontiers in Genetics aminoglycoside Evolutionary approaches Compensatory mutation Incomplete penetrance pathologic mutation Mitochondrial ribosomal RNA |
| title | An MRPS12 mutation modifies aminoglycoside sensitivity caused by 12S rRNA mutations |
| title_full | An MRPS12 mutation modifies aminoglycoside sensitivity caused by 12S rRNA mutations |
| title_fullStr | An MRPS12 mutation modifies aminoglycoside sensitivity caused by 12S rRNA mutations |
| title_full_unstemmed | An MRPS12 mutation modifies aminoglycoside sensitivity caused by 12S rRNA mutations |
| title_short | An MRPS12 mutation modifies aminoglycoside sensitivity caused by 12S rRNA mutations |
| title_sort | mrps12 mutation modifies aminoglycoside sensitivity caused by 12s rrna mutations |
| topic | aminoglycoside Evolutionary approaches Compensatory mutation Incomplete penetrance pathologic mutation Mitochondrial ribosomal RNA |
| url | http://journal.frontiersin.org/Journal/10.3389/fgene.2014.00469/full |
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