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

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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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Data availability

The data generated during the current study are available in the supplemental online content and from the corresponding author on request.

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Acknowledgements

We thank Dr. Hiroyuki Miyoshi of Keio University and RIKEN BioResource Center for the CS-CA-MCS plasmid. The authors are thankful to the Biomedical Research Center, Saitama Medical University for supporting to do the experiment. The authors thank Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript.

Funding

This work was supported in part by a grant of the “Practical Research Project for Rare/Intractable Diseases” (Fund ID: 18ek0109273s0102 and 18ek0109177s0103) and “Program for an Integrated Database of Clinical and Genomic Information” (Fund ID: 18kk0205002s9903) from Japan Agency for Medical Research and Development (AMED) (http://www.amed.go.jp/en/), and also MEXT-Supported Program for the Private University Research Branding Project. NNB is a recipient of the Uehara Memorial Foundation Research Fellowship. SCL is a JSPS International Research Fellow.

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Authors and Affiliations

  1. Diagnostics and Therapeutics of Intractable Diseases, Intractable Disease Research Center, Graduate School of Medicine, Juntendo University, Hongo 2-1-1, Bunkyo-ku, Tokyo, 113-8421, Japan

    Nurun Nahar Borna, Yoshihito Kishita, Masakazu Kohda, Sze Chern Lim, Kaoru Mogushi, Yukiko Yatsuka & Yasushi Okazaki

  2. Department of Metabolism, Chiba Children’s Hospital, Midori, Chiba, 266-0007, Japan

    Masaru Shimura, Takuya Fushimi, Keiko Ichimoto & Kei Murayama

  3. Laboratory for Comprehensive Genomic Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, 230-0045, Japan

    Yibo Wu & Yasushi Okazaki

  4. Department of Pediatrics, Saitama Medical University, Moroyama, Saitama, 350-0495, Japan

    Hiroko Harashima & Akira Ohtake

  5. Department of Pediatrics, Kumamoto City Hospital, Higashi-ku, Kumamoto, 862-8505, Japan

    Yuichiro Hisatomi

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  1. Nurun Nahar Borna
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Contributions

NNB, YK, and YO designed the study. Drafting of the manuscript was performed by NNB. NNB, SCL, MS, YW, YY, and HH acquired data. NNB, YK, MK, and KM analyzed data. TF and KI provided the patient’s clinical information. YH is the attending physician of the patient. YO, AO, and KM gave critical comments. YO led the project.

Corresponding author

Correspondence to Yasushi Okazaki.

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The authors declare that they have no conflict of interest.

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The study was approved by the ethics committee of Juntendo University and was performed after receiving written informed consent from the parents of the patient.

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Borna, N.N., Kishita, Y., Kohda, M. et al. Mitochondrial ribosomal protein PTCD3 mutations cause oxidative phosphorylation defects with Leigh syndrome. Neurogenetics 20, 9–25 (2019). https://doi.org/10.1007/s10048-018-0561-9

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