A high mutation load of m.14597A>G in MT-ND6 causes Leigh syndrome
Abstract 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 Leberʼs hereditary optic neuropathy (LHON) or dementia/dysarthria. In previous reports, less than 90% he...
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2021
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oai:doaj.org-article:2a76a814c3ba4c25adefbc26eb47bb7d2021-12-02T14:49:24ZA high mutation load of m.14597A>G in MT-ND6 causes Leigh syndrome10.1038/s41598-021-90196-52045-2322https://doaj.org/article/2a76a814c3ba4c25adefbc26eb47bb7d2021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-90196-5https://doaj.org/toc/2045-2322Abstract 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 Leberʼs 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.Yoshihito KishitaKaori IshikawaKazuto NakadaJun-Ichi HayashiTakuya FushimiMasaru ShimuraMasakazu KohdaAkira OhtakeKei MurayamaYasushi OkazakiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-6 (2021) |
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Medicine R Science Q Yoshihito Kishita Kaori Ishikawa Kazuto Nakada Jun-Ichi Hayashi Takuya Fushimi Masaru Shimura Masakazu Kohda Akira Ohtake Kei Murayama Yasushi Okazaki A high mutation load of m.14597A>G in MT-ND6 causes Leigh syndrome |
| description |
Abstract 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 Leberʼs 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. |
| format |
article |
| author |
Yoshihito Kishita Kaori Ishikawa Kazuto Nakada Jun-Ichi Hayashi Takuya Fushimi Masaru Shimura Masakazu Kohda Akira Ohtake Kei Murayama Yasushi Okazaki |
| author_facet |
Yoshihito Kishita Kaori Ishikawa Kazuto Nakada Jun-Ichi Hayashi Takuya Fushimi Masaru Shimura Masakazu Kohda Akira Ohtake Kei Murayama Yasushi Okazaki |
| author_sort |
Yoshihito Kishita |
| title |
A high mutation load of m.14597A>G in MT-ND6 causes Leigh syndrome |
| title_short |
A high mutation load of m.14597A>G in MT-ND6 causes Leigh syndrome |
| title_full |
A high mutation load of m.14597A>G in MT-ND6 causes Leigh syndrome |
| title_fullStr |
A high mutation load of m.14597A>G in MT-ND6 causes Leigh syndrome |
| title_full_unstemmed |
A high mutation load of m.14597A>G in MT-ND6 causes Leigh syndrome |
| title_sort |
high mutation load of m.14597a>g in mt-nd6 causes leigh syndrome |
| publisher |
Nature Portfolio |
| publishDate |
2021 |
| url |
https://doaj.org/article/2a76a814c3ba4c25adefbc26eb47bb7d |
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