New MT-ND6 and NDUFA1 mutations in mitochondrial respiratory chain disorders
Version of Record online: 28 APR 2014
© 2014 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Annals of Clinical and Translational Neurology
Volume 1, Issue 5, pages 361–369, May 2014
How to Cite
Uehara, N., Mori, M., Tokuzawa, Y., Mizuno, Y., Tamaru, S., Kohda, M., Moriyama, Y., Nakachi, Y., Matoba, N., Sakai, T., Yamazaki, T., Harashima, H., Murayama, K., Hattori, K., Hayashi, J.-I., Yamagata, T., Fujita, Y., Ito, M., Tanaka, M., Nibu, K.-i., Ohtake, A. and Okazaki, Y. (2014), New MT-ND6 and NDUFA1 mutations in mitochondrial respiratory chain disorders. Annals of Clinical and Translational Neurology, 1: 361–369. doi: 10.1002/acn3.59
- Issue online: 13 MAY 2014
- Version of Record online: 28 APR 2014
- Manuscript Accepted: 18 MAR 2014
- Manuscript Revised: 11 FEB 2014
- Manuscript Received: 11 DEC 2013
- Research Program of Innovative Cell Biology by Innovative Technology
- MEXT. Grant Numbers: A-22240072, B-21390459, A-25242062
- Ministry of Health, Labour and Welfare. Grant Numbers: H23-016, H23-119, H24-005
Mitochondrial respiratory chain disorder (MRCD) is an intractable disease of infants with variable clinical symptoms. Our goal was to identify the causative mutations in MRCD patients.
The subjects were 90 children diagnosed with MRCD by enzyme assay. We analyzed whole mitochondrial DNA (mtDNA) sequences. A cybrid study was performed in two patients. Whole exome sequencing was performed for one of these two patients whose mtDNA variant was confirmed as non-pathogenic.
Whole mtDNA sequences identified 29 mtDNA variants in 29 patients (13 were previously reported, the other 13 variants and three deletions were novel). The remaining 61 patients had no pathogenic mutations in their mtDNA. Of the 13 patients harboring unreported mtDNA variants, we excluded seven variants by manual curation. Of the remaining six variants, we selected two Leigh syndrome patients whose mitochondrial enzyme activity was decreased in their fibroblasts and performed a cybrid study. We confirmed that m.14439G>A (MT-ND6) was pathogenic, while m.1356A>G (mitochondrial 12S rRNA) was shown to be a non-pathogenic polymorphism. Exome sequencing and a complementation study of the latter patient identified a novel c.55C>T hemizygous missense mutation in the nuclear-encoded gene NDUFA1.
Our results demonstrate that it is important to perform whole mtDNA sequencing rather than only typing reported mutations. Cybrid assays are also useful to diagnose the pathogenicity of mtDNA variants, and whole exome sequencing is a powerful tool to diagnose nuclear gene mutations as molecular diagnosis can provide a lead to appropriate genetic counseling.