Journal Article

Molecular Phenotype of the np 7472 Deafness-Associated Mitochondrial Mutation in Osteosarcoma Cell Cybrids

Marina Toompuu, Valeria Tiranti, Massimo Zeviani and HowardT. Jacobs

in Human Molecular Genetics

Volume 8, issue 12, pages 2275-2283
Published in print November 1999 | ISSN: 0964-6906
Published online November 1999 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/8.12.2275
Molecular Phenotype of the np 7472 Deafness-Associated Mitochondrial Mutation in Osteosarcoma Cell Cybrids

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The nucleotide pair (np) 7472 insC mitochondrial DNA mutation in the tRNASer(UCN) gene is associated with sensorineural deafness, combined in some individuals with a wider syndrome including ataxia and myoclonus. 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 combination 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 tRNASer(UCN), but causes at most only a very mild and quantitative abnormality of mitochondrial 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 tRNASer(UCN), to which some cells of the auditory system are especially vulnerable.

Journal Article.  7028 words.  Illustrated.

Subjects: Genetics and Genomics

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