Abstract
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.
Highlights
PNPT1 encodes for polynucleotide phosphorylase (PNPase), a conserved homotrimeric 3 -to-5 exoribonuclease predominantly localized in the mitochondrial matrix and intermembrane space [1]
Functional studies were conducted in samples collected from four patients (P1, 2, 3, 4) in which the PNPT1 variants were identified by whole genome sequencing (WGS; Garvan Institute, Sydney) or whole exome sequencing (WES; Victorian Clinical Genetics Services (VCGS), Melbourne; Broad Institute, Cambridge, MA, USA; and Baylor College of Medicine, Houston, TX, USA)
PCR Quantification of Unprocessed Mitochondrial Transcripts qPCR for the quantification of unprocessed transcripts was performed with AccuPower 2X Greenstar qPCR Master Mix (Bioneer, Daejeon, Korea) using primers previously published by Matilainen and collaborators [9]
Summary
PNPT1 encodes for polynucleotide phosphorylase (PNPase), a conserved homotrimeric 3 -to-5 exoribonuclease predominantly localized in the mitochondrial matrix and intermembrane space [1]. It is primarily involved in mitochondrial RNA (mtRNA) processing and degradation [2]. Recent reports suggest that disrupted PNPase RNA processing could lead to the accumulation of double-stranded mtRNAs, with the possibility of triggering an altered immune response [6,7]. In a bid to better understand the clinical phenotype and functional consequences of patients with PNPT1-related diseases, we reported seven new patients with bi-allelic PNPT1 variants and expanded upon the mutational spectrum. We conducted functional studies and performed a thorough clinical review of previously published patients with PNPT1 variants [6,8,9,10,11,12,13]
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