BIOCHEMICAL-EVIDENCE FOR NUCLEAR GENE INVOLVEMENT PHENOTYPE OF NON-SYNDROMIC DEAFNESS ASSOCIATED WITH MITOCHONDRIAL 12S RIBOSOMAL-RNA MUTATION

The phenotypic effects of the human mitochondrial 12S rRNA gene mutati on at position 1555 associated with maternally inherited non-syndromic deafness and sensitivity to aminoglycoside-induced deafness have been analyzed in 25 lymphoblastoid cell lines derived from members of a la rge family carrying this mutation in homoplasmic form and from control individuals. A clear decrease in the rates of growth in galactose med ium, mitochondrial protein synthesis, total oxygen consumption, and co mplex I-, complex III- and complex IV-dependent respiration was observ ed in two groups of nine and 10 mutant cell lines derived, respectivel y, from symptomatic and asymptomatic members of the family, as compare d with six control cell lines. The severity of mitochondrial dysfuncti on in the mutant cell lines was correlated with the presence or absenc e of hearing loss in the donor individuals. These observations strongl y suggest a role of a nuclear factor(s) in the phenotypic manifestatio n of the mutation. The approach used here provides a paradigm for the analysis of the nuclear background involvement in other mtDNA-linked d isorders, including the putative ones associated with neurodegenerativ e diseases. Exposure of the cell lines derived from several symptomati c or asymptomatic individuals from the same family to high concentrati ons of neomycin or paromomycin decreased to a significant, nearly iden tical extent their rate of growth in glucose-containing medium, as con trasted with the unchanged growth rate of control cell lines or of mtD NA-less cells, These results support the hypothesis that the main targ et of the antibiotics is the mitochondrial 12S rRNA carrying the 1555 mutation, without any apparent role of the nuclear background.