Journal
SCIENTIFIC REPORTS
Volume 11, Issue 1, Pages -Publisher
NATURE RESEARCH
DOI: 10.1038/s41598-021-90196-5
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Funding
- AMED [JP18ek0109177, JP19ek0109273, JP20ek0109468, JP20kk0305015, JP19kk0205014, JP18kk0205002]
- MEXT
- JSPS KAKENHI [JP16K09973, KAKENHI JP19H03624]
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The study revealed that cells with a high mutation load of m.14597A>G lead to Leigh syndrome, rather than Lebers hereditary optic neuropathy or dementia/dysarthria.
Leigh syndrome (LS) is an early-onset progressive neurodegenerative disorder associated with mitochondrial deficiency. m.14597A>G (p.Ile26Thr) in the MT-ND6 gene was reported to cause Lebers hereditary optic neuropathy (LHON) or dementia/dysarthria. In previous reports, less than 90% heteroplasmy was shown to result in adult-onset disease. Here, by whole mitochondrial sequencing, we identified m.14597A>G mutation of a patient with LS. PCR-RFLP analysis on fibroblasts from the patient revealed a high mutation load (>90% heteroplasmy). We performed functional assays using cybrid cell models generated by fusing mtDNA-less rho0 HeLa cells with enucleated cells from patient fibroblasts carrying the m.14597A>G variant. Cybrid cell lines bearing the m.14597A>G variant exhibited severe effects on mitochondrial complex I activity. Additionally, impairment of cell proliferation, decreased ATP production and reduced oxygen consumption rate were observed in the cybrid cell lines bearing the m.14597A>G variant when the cells were metabolically stressed in medium containing galactose, indicating mitochondrial respiratory chain defects. These results suggest that a high mutation load of m.14597A>G leads to LS via a mitochondrial complex I defect, rather than LHON or dementia/dysarthria.
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