title: An MRPS12 mutation modifies aminoglycoside sensitivity caused by 12S rRNA mutations.
abstract: 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, 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.
authors: Departamento de Bioquímica, Biología Molecular y Celular, Universidad de Zaragoza Zaragoza, Spain ; Instituto de Investigación Sanitaria de Aragón, Universidad de Zaragoza Zaragoza, Spain ; Centros de Investigación Biomédica en Red de Enfermedades Raras, Universidad de Zaragoza Zaragoza, Spain.
authors: Sonia
authors: S
authors: Emperador
authors: Departamento de Bioquímica, Biología Molecular y Celular, Universidad de Zaragoza Zaragoza, Spain.
authors: David
authors: D
authors: Pacheu-Grau
authors: Departamento de Bioquímica, Biología Molecular y Celular, Universidad de Zaragoza Zaragoza, Spain.
authors: M Pilar
authors: MP
authors: Bayona-Bafaluy
authors: Departamento de Bioquímica, Biología Molecular y Celular, Universidad de Zaragoza Zaragoza, Spain.
authors: Nuria
authors: N
authors: Garrido-Pérez
authors: Departamento de Bioquímica, Biología Molecular y Celular, Universidad de Zaragoza Zaragoza, Spain.
authors: Antonio
authors: A
authors: Martín-Navarro
authors: Departamento de Bioquímica, Biología Molecular y Celular, Universidad de Zaragoza Zaragoza, Spain ; Instituto de Investigación Sanitaria de Aragón, Universidad de Zaragoza Zaragoza, Spain ; Centros de Investigación Biomédica en Red de Enfermedades Raras, Universidad de Zaragoza Zaragoza, Spain.
authors: Manuel J
authors: MJ
authors: López-Pérez
authors: Departamento de Bioquímica, Biología Molecular y Celular, Universidad de Zaragoza Zaragoza, Spain ; Instituto de Investigación Sanitaria de Aragón, Universidad de Zaragoza Zaragoza, Spain ; Centros de Investigación Biomédica en Red de Enfermedades Raras, Universidad de Zaragoza Zaragoza, Spain.
authors: Julio
authors: J
authors: Montoya
authors: Departamento de Bioquímica, Biología Molecular y Celular, Universidad de Zaragoza Zaragoza, Spain ; Instituto de Investigación Sanitaria de Aragón, Universidad de Zaragoza Zaragoza, Spain ; Centros de Investigación Biomédica en Red de Enfermedades Raras, Universidad de Zaragoza Zaragoza, Spain ; Fundación ARAID, Universidad de Zaragoza Zaragoza, Spain.
authors: Eduardo
authors: E
authors: Ruiz-Pesini
keywords: aminoglycoside; compensatory mutation; evolutionary approaches; incomplete penetrance; mitochondrial ribosomal RNA; mitochondrial ribosomal protein S12; pathologic mutation
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