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

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.

Leigh Syndrome Due to NDUFV1 Mutations Initially Presenting as LBSL

“…Exome analysis was performed as previously described [12]. Whole-exome sequencing was performed using the HiSeq2500 (Illumina, San Diego, CA, USA) platform, and for the alignment of the sequencing reads the NCBI human genome reference (GRCh37/hg19) was used.…”

“…Spectrophotometric enzyme activity assays using MT from fibroblasts and lentiviral-mediated transduced samples were performed as previously followed [12].…”

“…Total RNA isolation from fibroblasts, cDNA synthesis, and construction of plasmids were performed as described previously [12]. PCR was performed to amplify NDUFV1 (NM_007103.4) from control and subject's cDNA.…”

Intimate Relations—Mitochondria and Ageing

“…All of the RNA components of the mitochondrial translation machinery are encoded in mtDNA, the protein components of the ribosome and accessory proteins such as aminoacyl tRNA synthetases being nuclearly encoded. Mutations in nuclear genes encoding protein components of the ribosome affect the accuracy of translation and are associated with a diverse range of pathologies including ovarian insufficiency [ 260 ], encephalopathy [ 261 ], Leigh syndrome [ 262 ] and stress related behavioral alterations in mice [ 263 ]. A similar diversity of presentation is seen in mutations affecting mitochondrial aminoacyl tRNA synthetases and the reasons for this diversity from an apparently similar mechanism are discussed by González-Serrano [ 264 ].…”

Data-Independent Acquisition-Based Quantitative Proteomic Analysis of m.3243A>G MELAS Reveals Novel Potential Pathogenesis and Therapeutic Targets

“…A study of PTCD3 knockdown showed protein synthesis was seriously disturbed to result in OXPHOS de ciency, although no effect on RNA metabolism 41 . PTCD3 mutations led to impaired translation of mtDNA-encoded proteins, resulting in combined defects of Complex I and IV, and decreased ATP production 42 . Although MRPL4 had not been reported in the mitochondrial diseases, this molecule had attracted increasing attention from researchers because it had been reported to be downstream of hypoxia-inducible factor-1α (HIF-1α) 43 .…”