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

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 caus...

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Autores principales: Rius, Rocio, Van Bergen, Nicole J., Compton, Alison G., Riley, Lisa G., Kava, Maina P., Balasubramaniam, Shanti, Amor, David J., Fanjul-Fernandez, Miriam, Cowley, Mark J., Fahey, Michael C., Koenig, Mary K., Enns, Gregory M., Sadedin, Simon, Wilson, Meredith J., Tan, Tiong Y., Thorburn, David R., Christodoulou, John
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6912252/
https://www.ncbi.nlm.nih.gov/pubmed/31752325
http://dx.doi.org/10.3390/jcm8112020
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author Rius, Rocio
Van Bergen, Nicole J.
Compton, Alison G.
Riley, Lisa G.
Kava, Maina P.
Balasubramaniam, Shanti
Amor, David J.
Fanjul-Fernandez, Miriam
Cowley, Mark J.
Fahey, Michael C.
Koenig, Mary K.
Enns, Gregory M.
Sadedin, Simon
Wilson, Meredith J.
Tan, Tiong Y.
Thorburn, David R.
Christodoulou, John
author_facet Rius, Rocio
Van Bergen, Nicole J.
Compton, Alison G.
Riley, Lisa G.
Kava, Maina P.
Balasubramaniam, Shanti
Amor, David J.
Fanjul-Fernandez, Miriam
Cowley, Mark J.
Fahey, Michael C.
Koenig, Mary K.
Enns, Gregory M.
Sadedin, Simon
Wilson, Meredith J.
Tan, Tiong Y.
Thorburn, David R.
Christodoulou, John
author_sort Rius, Rocio
collection PubMed
description 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.
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spelling pubmed-69122522020-01-02 Clinical Spectrum and Functional Consequences Associated with Bi-Allelic Pathogenic PNPT1 Variants Rius, Rocio Van Bergen, Nicole J. Compton, Alison G. Riley, Lisa G. Kava, Maina P. Balasubramaniam, Shanti Amor, David J. Fanjul-Fernandez, Miriam Cowley, Mark J. Fahey, Michael C. Koenig, Mary K. Enns, Gregory M. Sadedin, Simon Wilson, Meredith J. Tan, Tiong Y. Thorburn, David R. Christodoulou, John J Clin Med Article 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. MDPI 2019-11-19 /pmc/articles/PMC6912252/ /pubmed/31752325 http://dx.doi.org/10.3390/jcm8112020 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Rius, Rocio
Van Bergen, Nicole J.
Compton, Alison G.
Riley, Lisa G.
Kava, Maina P.
Balasubramaniam, Shanti
Amor, David J.
Fanjul-Fernandez, Miriam
Cowley, Mark J.
Fahey, Michael C.
Koenig, Mary K.
Enns, Gregory M.
Sadedin, Simon
Wilson, Meredith J.
Tan, Tiong Y.
Thorburn, David R.
Christodoulou, John
Clinical Spectrum and Functional Consequences Associated with Bi-Allelic Pathogenic PNPT1 Variants
title Clinical Spectrum and Functional Consequences Associated with Bi-Allelic Pathogenic PNPT1 Variants
title_full Clinical Spectrum and Functional Consequences Associated with Bi-Allelic Pathogenic PNPT1 Variants
title_fullStr Clinical Spectrum and Functional Consequences Associated with Bi-Allelic Pathogenic PNPT1 Variants
title_full_unstemmed Clinical Spectrum and Functional Consequences Associated with Bi-Allelic Pathogenic PNPT1 Variants
title_short Clinical Spectrum and Functional Consequences Associated with Bi-Allelic Pathogenic PNPT1 Variants
title_sort clinical spectrum and functional consequences associated with bi-allelic pathogenic pnpt1 variants
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6912252/
https://www.ncbi.nlm.nih.gov/pubmed/31752325
http://dx.doi.org/10.3390/jcm8112020
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