Cargando…
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...
Autores principales: | , , , , , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1783479411976175616 |
---|---|
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. |
format | Online Article Text |
id | pubmed-6912252 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT riusrocio clinicalspectrumandfunctionalconsequencesassociatedwithbiallelicpathogenicpnpt1variants AT vanbergennicolej clinicalspectrumandfunctionalconsequencesassociatedwithbiallelicpathogenicpnpt1variants AT comptonalisong clinicalspectrumandfunctionalconsequencesassociatedwithbiallelicpathogenicpnpt1variants AT rileylisag clinicalspectrumandfunctionalconsequencesassociatedwithbiallelicpathogenicpnpt1variants AT kavamainap clinicalspectrumandfunctionalconsequencesassociatedwithbiallelicpathogenicpnpt1variants AT balasubramaniamshanti clinicalspectrumandfunctionalconsequencesassociatedwithbiallelicpathogenicpnpt1variants AT amordavidj clinicalspectrumandfunctionalconsequencesassociatedwithbiallelicpathogenicpnpt1variants AT fanjulfernandezmiriam clinicalspectrumandfunctionalconsequencesassociatedwithbiallelicpathogenicpnpt1variants AT cowleymarkj clinicalspectrumandfunctionalconsequencesassociatedwithbiallelicpathogenicpnpt1variants AT faheymichaelc clinicalspectrumandfunctionalconsequencesassociatedwithbiallelicpathogenicpnpt1variants AT koenigmaryk clinicalspectrumandfunctionalconsequencesassociatedwithbiallelicpathogenicpnpt1variants AT ennsgregorym clinicalspectrumandfunctionalconsequencesassociatedwithbiallelicpathogenicpnpt1variants AT sadedinsimon clinicalspectrumandfunctionalconsequencesassociatedwithbiallelicpathogenicpnpt1variants AT wilsonmeredithj clinicalspectrumandfunctionalconsequencesassociatedwithbiallelicpathogenicpnpt1variants AT tantiongy clinicalspectrumandfunctionalconsequencesassociatedwithbiallelicpathogenicpnpt1variants AT thorburndavidr clinicalspectrumandfunctionalconsequencesassociatedwithbiallelicpathogenicpnpt1variants AT christodouloujohn clinicalspectrumandfunctionalconsequencesassociatedwithbiallelicpathogenicpnpt1variants |