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A biochemical basis for the inherited susceptibility to aminoglycoside ototoxicity

Guan, Min-Xin and Fischel-Ghodsian, Nathan and Attardi, Giuseppe (2000) A biochemical basis for the inherited susceptibility to aminoglycoside ototoxicity. Human Molecular Genetics, 9 (12). pp. 1787-1793. ISSN 0964-6906. http://resolver.caltech.edu/CaltechAUTHORS:20111205-082740037

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Abstract

The A1555 G mutation in mitochondrial 12S rRNA has been found to be associated with non-syndromic deafness and aminoglycoside-induced deafness. The sensitivity to the aminoglycoside paromomycin has been analyzed in lymphoblastoid cell lines derived from five deaf individuals and five hearing individuals from an Arab-Israeli family carrying the A1555G mutation, and three married-in controls from the same family. Exposure to a high concentration of paromomycin (2 mg/ml), which caused an 8% average increase in doubling time (DT) in the control cell lines, produced higher average DT increases (49 and 47%) in the A1555G mutation-carrying cell lines derived from symptomatic and asymptomatic individuals, respectively. The ratios of translation rates in the presence and absence of paromomycin, which reflected the effect of the drug on mitochondrial protein synthesis, were significantly decreased in the cell lines derived from symptomatic and asymptomatic individuals (by 30 and 28% on average, respectively), compared with the ratios in the control cell lines. These ratios showed, in both groups of mutant cell lines, a significant negative correlation with the ratios of DTs in the presence and absence of the antibiotic. These results have provided the first direct evidence that the mitochondrial 12S rRNA carrying the A1555G mutation is the main target of aminoglycosides. They suggest that these antibiotics exert their detrimental effect through an alteration of mitochondrial protein synthesis, which exacerbates the inherent defect caused by the mutation, reducing the overall translation rate down to and below the minimal level required for normal cellular function (40–50%).


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1093/hmg/9.12.1787DOIUNSPECIFIED
http://hmg.oxfordjournals.org/content/9/12/1787.abstractPublisherUNSPECIFIED
Additional Information:© 2000 Oxford University Press. Received 11 March 2000; Revised and Accepted 31 May 2000. These investigations were supported by a Start-up Fund from Children’s Hospital Medical Center in Cincinnati to M.-X.G., research grant no. 5R01 DC01402-04 to N.F.-G. from the National Institute on Deafness and Other Communication Disorders, NIH, and NIH grant no. GM11726 to G.A. We are grateful to Dr Anne Chomyn for help in the statistical analysis and for critically reading the manuscript, we thank Benneta Keeley, Arger Drew and Rosario Zedan for technical assistance, and Debbie Williams for clerical support.
Funders:
Funding AgencyGrant Number
Children’s Hospital Medical Center Cincinnati 5R01 DC01402-04
National Institute on Deafness and Other Communication DisordersUNSPECIFIED
NIHGM11726
Record Number:CaltechAUTHORS:20111205-082740037
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20111205-082740037
Official Citation: Min-Xin Guan, Nathan Fischel-Ghodsian, and Giuseppe Attardi A biochemical basis for the inherited susceptibility to aminoglycoside ototoxicity Hum. Mol. Genet. (2000) 9(12): 1787-1793 doi:10.1093/hmg/9.12.1787
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:28288
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:05 Dec 2011 17:08
Last Modified:05 Dec 2011 17:08

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