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03.01.2019 | Original Article

Mitochondrial ribosomal protein PTCD3 mutations cause oxidative phosphorylation defects with Leigh syndrome

verfasst von: Nurun Nahar Borna, Yoshihito Kishita, Masakazu Kohda, Sze Chern Lim, Masaru Shimura, Yibo Wu, Kaoru Mogushi, Yukiko Yatsuka, Hiroko Harashima, Yuichiro Hisatomi, Takuya Fushimi, Keiko Ichimoto, Kei Murayama, Akira Ohtake, Yasushi Okazaki

Erschienen in: Neurogenetics | Ausgabe 1/2019

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Abstract

Pentatricopeptide repeat domain proteins are a large family of RNA-binding proteins involved in mitochondrial RNA editing, stability, and translation. Mitochondrial translation machinery defects are an expanding group of genetic diseases in humans. We describe a patient who presented with low birth weight, mental retardation, and optic atrophy. Brain MRI showed abnormal bilateral signals at the basal ganglia and brainstem, and the patient was diagnosed as Leigh syndrome. Exome sequencing revealed two potentially loss-of-function variants [c.415-2A>G, and c.1747_1748insCT (p.Phe583Serfs*3)] in PTCD3 (also known as MRPS39). PTCD3, a member of the pentatricopeptide repeat domain protein family, is a component of the small mitoribosomal subunit. The patient had marked decreases in mitochondrial complex I and IV levels and activities, oxygen consumption and ATP biosynthesis, and generalized mitochondrial translation defects in fibroblasts. Quantitative proteomic analysis revealed decreased levels of the small mitoribosomal subunits. Complementation experiments rescued oxidative phosphorylation complex I and IV levels and activities, ATP biosynthesis, and MT-RNR1 rRNA transcript level, providing functional validation of the pathogenicity of identified variants. This is the first report of an association of PTCD3 mutations with Leigh syndrome along with combined oxidative phosphorylation deficiencies caused by defects in the mitochondrial translation machinery.

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Titel: Mitochondrial ribosomal protein PTCD3 mutations cause oxidative phosphorylation defects with Leigh syndrome
verfasst von: Nurun Nahar Borna
Yoshihito Kishita
Masakazu Kohda
Sze Chern Lim
Masaru Shimura
Yibo Wu
Kaoru Mogushi
Yukiko Yatsuka
Hiroko Harashima
Yuichiro Hisatomi
Takuya Fushimi
Keiko Ichimoto
Kei Murayama
Akira Ohtake
Yasushi Okazaki
Publikationsdatum: 03.01.2019
Verlag: Springer Berlin Heidelberg
Erschienen in: Neurogenetics / Ausgabe 1/2019
Print ISSN: 1364-6745
Elektronische ISSN: 1364-6753
DOI: https://doi.org/10.1007/s10048-018-0561-9

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Mitochondrial ribosomal protein PTCD3 mutations cause oxidative phosphorylation defects with Leigh syndrome

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