CPEO (chronic progressive external ophthalmoplegia) is a common mitochondrial disease phenotype in adults which is due to mtDNA (mitochondrial DNA) point mutations in a subset of patients. Attributing pathogenicity to novel tRNA mtDNA mutations still poses a challenge, particularly when several mtDNA sequence variants are present. In the present study we report a CPEO patient for whom sequencing of the mitochondrial genome revealed three novel tRNA mtDNA mutations: G5835A, del4315A, T1658C in tRNATyr, tRNAIle and tRNAVal genes. In skeletal muscle, the tRNAVal and tRNAIle mutations were homoplasmic, whereas the tRNATyr mutation was heteroplasmic. To address the pathogenic relevance, we performed two types of functional tests: (i) single skeletal muscle fibre analysis comparing G5835A mutation loads and biochemical phenotypes of corresponding fibres, and (ii) Northern-blot analyses of mitochondrial tRNATyr, tRNAIle and tRNAVal. We demonstrated that both the G5835A tRNATyr and del4315A tRNAIle mutation have serious functional consequences. Single-fibre analyses displayed a high threshold of the tRNATyr mutation load for biochemical phenotypic expression at the single-cell level, indicating a rather mild pathogenic effect. In contrast, skeletal muscle tissue showed a severe decrease in respiratory-chain activities, a reduced overall COX (cytochrome c oxidase) staining intensity and abundant COX-negative fibres. Northern-blot analyses showed a dramatic reduction of tRNATyr and tRNAIle levels in muscle, with impaired charging of tRNAIle, whereas tRNAVal levels were only slightly decreased, with amino-acylation unaffected. Our findings suggest that the heteroplasmic tRNATyr and homoplasmic tRNAIle mutation act together, resulting in a concerted effect on the biochemical and histological phenotype. Thus homoplasmic mutations may influence the functional consequences of pathogenic heteroplasmic mtDNA mutations.
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Research Article|
April 29 2008
Concerted action of two novel tRNA mtDNA point mutations in chronic progressive external ophthalmoplegia
Cornelia Kornblum;
Cornelia Kornblum
* Department of Neurology, University of Bonn Medical Center, Bonn, D-53105, Germany
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Gábor Zsurka;
Gábor Zsurka
† Department of Epileptology, University of Bonn Medical Center, Bonn, D-53105, Germany
‡ Platform NeuroCognition, Life and Brain Center, Bonn, D-53105, Germany
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Rudolf J. Wiesner;
Rudolf J. Wiesner
§ Institute of Vegetative Physiology, Faculty of Medicine, University of Köln, Köln, D-50931, Germany
∥ Center for Molecular Medicine Cologne (CMMC), University of Köln, Köln, D-50931, Germany
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Rolf Schröder;
Rolf Schröder
¶ Department of Neuropathology, University of Erlangen, Erlangen, D-91054, Germany
** Department of Neurology, University of Erlangen, Erlangen, D-91054, Germany
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Wolfram S. Kunz
Wolfram S. Kunz
1
† Department of Epileptology, University of Bonn Medical Center, Bonn, D-53105, Germany
‡ Platform NeuroCognition, Life and Brain Center, Bonn, D-53105, Germany
1 To whom correspondence should be addressed ([email protected]).
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Publisher: Portland Press Ltd
Received:
January 17 2008
Revision Received:
March 25 2008
Accepted:
April 03 2008
Accepted Manuscript online:
April 03 2008
Online ISSN: 1573-4935
Print ISSN: 0144-8463
© The Authors Journal compilation © 2008 Biochemical Society
2008
Biosci Rep (2008) 28 (2): 89–96.
Article history
Received:
January 17 2008
Revision Received:
March 25 2008
Accepted:
April 03 2008
Accepted Manuscript online:
April 03 2008
Citation
Cornelia Kornblum, Gábor Zsurka, Rudolf J. Wiesner, Rolf Schröder, Wolfram S. Kunz; Concerted action of two novel tRNA mtDNA point mutations in chronic progressive external ophthalmoplegia. Biosci Rep 1 April 2008; 28 (2): 89–96. doi: https://doi.org/10.1042/BSR20080004
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