ArticleEuropean journal of human genetics : EJHG2017
Whole-exome sequencing identifies novel variants in PNPT1 causing oxidative phosphorylation defects and severe multisystem disease.
Article in European journal of human genetics : EJHG, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 37 citations in OpenAlex.
- JAK Inhibition inJIMD reports · 2026Article
- Characterization of Mitochondrial Double-Stranded RNA Levels in Non-Small Cell Lung Carcinoma.Cancer research communications · 2026Article
- Human polynucleotide phosphorylase in mitochondrial RNA metabolism.Bioscience reports · 2025Review
- A novel polyribonucleotide nucleotidyltransferase 1 (Translational pediatrics · 2025Article
- Structural insights into human PNPase in health and disease.Nucleic acids research · 2025Article
- Heterozygous PNPT1 Variants Cause a Sensory Ataxic Neuropathy.European journal of neurology · 2025Article
- Article
- An Integrated Computational Analysis of High-Risk SNPs in Angiopoietin-like Proteins (ANGPTL3 and ANGPTL8) Reveals Perturbed Protein Dynamics Associated with Cancer.Molecules (Basel, Switzerland) · 2023Article
- SUV3 Helicase and Mitochondrial Homeostasis.International journal of molecular sciences · 2023Review
- Polynucleotide phosphorylase protects against renal tubular injury via blocking mt-dsRNA-PKR-eIF2α axis.Nature communications · 2023Article
- TEFM variants impair mitochondrial transcription causing childhood-onset neurological disease.Nature communications · 2023Article
- SP1 and NFY Regulate the Expression ofInternational journal of molecular sciences · 2022Article
- RNA Granules in the Mitochondria and Their Organization under Mitochondrial Stresses.International journal of molecular sciences · 2021Review
- Type I Interferonopathies: from a Novel Concept to Targeted Therapeutics.Current rheumatology reports · 2020Review
- Clinical Spectrum and Functional Consequences Associated with Bi-Allelic PathogenicJournal of clinical medicine · 2019Article
- AWESOME: a database of SNPs that affect protein post-translational modifications.Nucleic acids research · 2019Article
- Polynucleotide phosphorylase: Not merely an RNase but a pivotal post-transcriptional regulator.PLoS genetics · 2018Review
- Crystal structure of dimeric human PNPase reveals why disease-linked mutants suffer from low RNA import and degradation activities.Nucleic acids research · 2018Article
- Mitochondrial DNA transcription and translation: clinical syndromes.Essays in biochemistry · 2018Review
- Dedicated surveillance mechanism controls G-quadruplex forming non-coding RNAs in human mitochondria.Nature communications · 2018Article
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Authors and funding
10 authors at 5 institutions in 3 countries.
Funding
Abstract
Recent advances in next-generation sequencing strategies have led to the discovery of many novel disease genes. We describe here a non-consanguineous family with two affected boys presenting with early onset of severe axonal neuropathy, optic atrophy, intellectual disability, auditory neuropathy and chronic respiratory and gut disturbances. Whole-exome sequencing (WES) was performed on all family members and we identified compound heterozygous variants (c.[760C>A];[1528G>C];p.[(Gln254Lys);(Ala510Pro)] in the polyribonucleotide nucleotidyltransferase 1 (PNPT1) gene in both affected individuals. PNPT1 encodes the polynucleotide phosphorylase (PNPase) protein, which is involved in the transport of small RNAs into the mitochondria. These RNAs are involved in the mitochondrial translation machinery, responsible for the synthesis of mitochondrially encoded subunits of the oxidative phosphorylation (OXPHOS) complexes. Both PNPT1 variants are within highly conserved regions and predicted to be damaging. These variants resulted in quaternary defects in the PNPase protein and a clear reduction in protein and mRNA expression of PNPT1 in patient fibroblasts compared with control cells. Protein analysis of the OXPHOS complexes showed a significant reduction in complex I (CI), complex III (CIII) and complex IV (CIV). Enzyme activity of CI and CIV was clearly reduced in patient fibroblasts compared with controls along with a 33% reduction in total mitochondrial protein synthesis. In vitro rescue experiments, using exogenous expression of wild-type PNPT1 in patient fibroblasts, ameliorated the deficiencies in the OXPHOS complex protein expression, supporting the likely pathogenicity of these variants and the importance of WES in efficiently identifying rare genetic disease genes.
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Registered trials
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