Clinical Spectrum and Functional Consequences Associated with Bi-Allelic Pathogenic PNPT1 Variants

Rocio Rius, Nicole J. Van Bergen, Alison G Compton, Lisa G Riley, Maina P. Kava, Shanti Balasubramaniam, David J Amor, Miriam Fanjul-Fernández, Mark J Cowley, Michael C Fahey, Mary K. Koenig , Gregory M. Enns, Simon P. Sadedin, Meredith J. Wilson, Tiong Y Tan, David Ross Thorburn, John Christodoulou

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PNPT1 (PNPase—polynucleotide phosphorylase) is involved in multiple RNA processing functions in the mitochondria. Bi-allelic pathogenic PNPT1 variants cause heterogeneous clinical phenotypes affecting multiple organs without any established genotype–phenotype correlations. Defects in PNPase can cause variable combined respiratory chain complex defects. Recently, it has been suggested that PNPase can lead to activation of an innate immune response. To better understand the clinical and molecular spectrum of patients with bi-allelic PNPT1 variants, we captured detailed clinical and molecular phenotypes of all 17 patients reported in the literature, plus seven new patients, including a 78-year-old male with the longest reported survival. A functional follow-up of genomic sequencing by cDNA studies confirmed a splicing defect in a novel, apparently synonymous, variant. Patient fibroblasts showed an accumulation of mitochondrial unprocessed PNPT1 transcripts, while blood showed an increased interferon response. Our findings suggest that functional analyses of the RNA processing function of PNPase are more sensitive than testing downstream defects in oxidative phosphorylation (OXPHPOS) enzyme activities. This research extends our knowledge of the clinical and functional consequences of bi-allelic pathogenic PNPT1 variants that may guide management and further efforts into understanding the pathophysiological mechanisms for therapeutic development.

Original languageEnglish
Article number2020
Number of pages11
JournalJournal of Clinical Medicine
Issue number11
Publication statusPublished - Nov 2019


  • Interferon
  • Mitochondrial
  • mutation
  • NPPase
  • PNPT1
  • Respiratory chain
  • Splice defect

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