Human Molecular Genetics, Vol 8, 2275-2283, Copyright © 1999 by Oxford University Press
M Toompuu, V Tiranti, M Zeviani and HT Jacobs
The nucleotide pair (np) 7472 insC mitochondrial DNA mutation in the
tRNA(Ser)(UCN) gene is associated with sensorineural deafness, combined in
some individuals with a wider syndrome including ataxia and myo- clonus.
Previous studies in osteosarcoma cell cybrids revealed only a mild
respiratory defect linked to the mutation. We have investigated the
biochemical and molecular consequences of the mutation, using a panel of
seven osteosarcoma cell cybrids containing 100% mutant mtDNA, plus two
cybrids carrying 100% wild-type mtDNA from the same patient. The mutation
is associated with a mild growth deficit in selective (galactose) medium
that is only significant in com-bination with a reduced mtDNA copy number,
suggesting a mechanism that might modulate clinical phenotype. The mutation
results in a 65% drop in the steady- state level of tRNA(Ser)(UCN), but
causes at most only a very mild and quantitative abnormality of
mito-chondrial protein synthesis, associated with modest hypersensitivity
to doxycyclin. No evidence for a specific defect in aminoacylation was
obtained, and unlike the case with the np 7445 mutation, the pattern of RNA
processing of light strand transcripts of the ND6 region was not
systematically altered. Comparing the np 7472 and np 7445 mutant phenotypes
in cultured cells suggests that sensorineural deafness can result from a
functional insufficiency of mitochondrial tRNA(Ser)(UCN), to which some
cells of the auditory system are especially vulnerable.
ARTICLES
Molecular phenotype of the np 7472 deafness-associated mitochondrial mutation in osteosarcoma cell cybrids
Institute of Medical Technology and Tampere University Hospital, University of Tampere, PO Box 607, 33101 Tampere, Finland,
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