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Nuclear background determines biochemical phenotype in the deafness-associated mitochondrial 12S rRNA mutation

Guan, Min-Xin and Fischel-Ghodsian, Nathan and Attardi, Giuseppe (2001) Nuclear background determines biochemical phenotype in the deafness-associated mitochondrial 12S rRNA mutation. Human Molecular Genetics, 10 (6). pp. 573-580. ISSN 0964-6906. doi:10.1093/hmg/10.6.573.

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The pathogenetic mechanism of the human mitochondrial 12S rRNA gene mutation at position 1555, associated with non-syndromic deafness and aminoglycoside-induced deafness, has been investigated in 33 transformants obtained by transferring mitochondria from lymphoblastoid cell lines into human mitochondrial DNA (mtDNA)-less (ρ°206) cells. In this nearly constant nuclear background, 15 transformants derived from five symptomatic individuals from a large Arab-Israeli family, carrying this mutation in homoplasmic form, exhibited significant decreases compared with nine control transformants in the rate of growth in a medium containing galactose instead of glucose, as well as in the rates of mitochondrial protein synthesis and of substrate-dependent respiration. Most significantly, these decreases were very similar to those observed in nine transformants derived from three asymptomatic members of the family. This result in transmitochondrial cybrids is in contrast to the differences in the same parameters previously demonstrated between the original lymphoblastoid cell lines derived from the symptomatic and asymptomatic members of the Arab-Israeli family. In addition, the intragroup variability in biochemical dysfunction among the lymphoblastoid cell lines from different symptomatic or asymptomatic or control individuals was significantly reduced in the derived mitochondrial transformants carrying the same nuclear background. These observations provide strong genetic and biochemical evidence in support of the idea that the nuclear background plays a determinant role in the phenotypic manifestation of the non-syndromic deafness associated with the A1555G mutation.

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Additional Information:© 2001 Oxford University Press. Received 3 November 2000; Revised and Accepted 22 January 2001. We thank Dr Anne Chomyn for invaluable discussion, and Benneta Keeley, Arger Drew and Rosario Zedan for technical assistance. These investigations were supported by a Starting-up Fund from the Children’s Hospital Medical Center in Cincinnati to M.-X.G., N.I.H. grant 5RO1 DC0140204 to N.F.-G. from the National Institute on Deafness and Other Communication Disorders and N.I.H. grant GM11726 to G.A.
Funding AgencyGrant Number
Children’s Hospital Medical Center CincinnatiUNSPECIFIED
National Institute on Deafness and Other Communication Disorders5RO1 DC0140204
Issue or Number:6
Record Number:CaltechAUTHORS:20111117-114319907
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Official Citation: Min-Xin Guan, Nathan Fischel-Ghodsian, and Giuseppe Attardi Nuclear background determines biochemical phenotype in the deafness-associated mitochondrial 12S rRNA mutation Hum. Mol. Genet. (2001) 10(6): 573-580 doi:10.1093/hmg/10.6.573
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:27833
Deposited By: Ruth Sustaita
Deposited On:17 Nov 2011 20:47
Last Modified:09 Nov 2021 16:52

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