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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Auteurs principaux:	Yoshihito Kishita, Kaori Ishikawa, Kazuto Nakada, Jun-Ichi Hayashi, Takuya Fushimi, Masaru Shimura, Masakazu Kohda, Akira Ohtake, Kei Murayama, Yasushi Okazaki
Format:	article
Langue:	EN
Publié:	Nature Portfolio 2021
Sujets:	Medicine R Science Q
Accès en ligne:	https://doaj.org/article/2a76a814c3ba4c25adefbc26eb47bb7d
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spelling	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)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	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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A high mutation load of m.14597A>G in MT-ND6 causes Leigh syndrome

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