2. Academic Validation
  3. Mitochondrial ribosomal protein PTCD3 mutations cause oxidative phosphorylation defects with Leigh syndrome

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

  • Neurogenetics. 2019 Mar;20(1):9-25. doi: 10.1007/s10048-018-0561-9.
Nurun Nahar Borna 1,  Yoshihito Kishita 1,  Masakazu Kohda 1,  Sze Chern Lim 1,  Masaru Shimura 2,  Yibo Wu 3,  Kaoru Mogushi 1,  Yukiko Yatsuka 1,  Hiroko Harashima 4,  Yuichiro Hisatomi 5,  Takuya Fushimi 2,  Keiko Ichimoto 2,  Kei Murayama 2,  Akira Ohtake 4,  Yasushi Okazaki 6 7
Affiliations

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.
  • 2 Department of Metabolism, Chiba Children's Hospital, Midori, Chiba, 266-0007, Japan.
  • 3 Laboratory for Comprehensive Genomic Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, 230-0045, Japan.
  • 4 Department of Pediatrics, Saitama Medical University, Moroyama, Saitama, 350-0495, Japan.
  • 5 Department of Pediatrics, Kumamoto City Hospital, Higashi-ku, Kumamoto, 862-8505, Japan.
  • 6 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. [email protected].
  • 7 Laboratory for Comprehensive Genomic Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, 230-0045, Japan. [email protected].
PMID: 30607703 DOI: 10.1007/s10048-018-0561-9
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.

Keywords

Leigh syndrome; Mitochondrial translation; Oxidative phosphorylation; PTCD3; Small mitoribosomal subunit.

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