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Lookup NU author(s): Dr Margaret Johnson, Professor Zofia Chrzanowska-LightowlersORCiD, Professor Robert Lightowlers
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We report the clinical, biochemical, and genetic investigation of a patient with a severe mitochondrial encephalomyopathy. Genetic studies identified a novel, heteroplasmic tRNA mutation at nt 10010. This T→C transition is located in the DHU loop of mitochondrial tRNA(GLY). In skeletal muscle, it was present at lower levels in cytochrome c oxidase (COX)-normal (87.2% ± 11%) compared with COX-deficient fibers (97.3% ± 2.6%); it was found in skin fibroblasts and blood cells, but at lower levels of heteroplasmy (15% ± 6% and 17% ± 10%, respectively). A second, heteroplasmic transition (A→G), at nt 5656, showed a different distribution than the tRNA(GLY) mutation, with very low levels in skeletal muscle (<3%) but higher levels in blood (22.7% + 3%) and skin fibroblasts (21% ± 2%). These transitions were followed both in vivo, by repeat biopsy and blood sampling, and in vitro, by establishing primary cultures of myoblasts and skin fibroblasts. Repeat muscle biopsy showed a dramatic increase in COX- deficient fibers, but not of the tRNA(GLY) mutation. Indeed, no significant change in heteroplasmy was measured for either substitution in muscle or blood. In vitro analysis gave very different results. The T10010C was not found in cultured myoblasts, even at early passage. In uncloned fibroblasts, the T10010C was stable (~10%) for several passages but then gradually was lost. In contrast, the A5656G rose progressively from 27% to 91%. In cloned fibroblasts, different combinations of both base-pair changes and wild type could be identified, confirming the presence of clonal, intracellular triplasmy.
Author(s): Bidooki SK, Johnson MA, Chrzanowska-Lightowlers Z, Bindoff LA, Lightowlers RN
Publication type: Article
Publication status: Published
Journal: American Journal of Human Genetics
Year: 1997
Volume: 60
Issue: 6
Pages: 1430-1438
Print publication date: 01/06/1997
ISSN (print): 0002-9297
ISSN (electronic): 1537-6605
Publisher: Cell Press
URL: http://dx.doi.org/10.1086/515460
DOI: 10.1086/515460
PubMed id: 9199564
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