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Article

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

1
Murdoch Children’s Research Institute, Melbourne, VIC 3052, Australia
2
Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia
3
Kids Research, The Children’s Hospital at Westmead, Sydney, NSW 2145, Australia
4
Discipline of Child & Adolescent Health, Sydney Medical School, University of Sydney, Sydney, NSW 2050, Australia
5
Department of Neurology, Perth Children’s Hospital, Perth, WA 6009, Australia
6
Department of Metabolic Medicine and Rheumatology, Perth Children’s Hospital, Perth, WA 6009, Australia
7
Genetic Metabolic Disorders Service, Western Sydney Genetics Program, The Children’s Hospital at Westmead, Sydney, NSW 2145, Australia
8
Discipline of Genetic Medicine, Sydney Medical School, University of Sydney, Sydney, NSW 2145, Australia
9
Victorian Clinical Genetic Services, Melbourne, VIC 3052, Australia
10
Precision Medicine Theme, Children’s Cancer Institute, Kensington, NSW 2750, Australia
11
Kinghorn Centre for Clinical Genomics, Garvan Institute, University of New South Wales, Randwick, NSW 2010, Australia
12
School of Women’s and Children’s Health, University of New South Wales, Randwick, NSW 2031, Australia
13
Department of Paediatrics, Monash University, Melbourne, VIC 3168, Australia
14
The University of Texas McGovern Medical School, Houston, TX 77030, USA
15
Department of Pediatrics, Division of Medical Genetics, Stanford University, Stanford, CA 94305, USA
16
Department of Clinical Genetics, The Children’s Hospital at Westmead, Sydney, NSW 2145, Australia
17
Discipline of Genomic Medicine, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia
*
Author to whom correspondence should be addressed.
J. Clin. Med. 2019, 8(11), 2020; https://doi.org/10.3390/jcm8112020
Received: 9 October 2019 / Revised: 11 November 2019 / Accepted: 14 November 2019 / Published: 19 November 2019
(This article belongs to the Special Issue The Rise of Mitochondria in Medicine)
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. View Full-Text
Keywords: mitochondrial; PNPT1; PNPase; interferon; OXPHOS; respiratory chain; mutation; splice defect mitochondrial; PNPT1; PNPase; interferon; OXPHOS; respiratory chain; mutation; splice defect
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MDPI and ACS Style

Rius, R.; Van Bergen, N.J.; Compton, A.G.; Riley, L.G.; Kava, M.P.; Balasubramaniam, S.; Amor, D.J.; Fanjul-Fernandez, M.; Cowley, M.J.; Fahey, M.C.; Koenig, M.K.; Enns, G.M.; Sadedin, S.; Wilson, M.J.; Tan, T.Y.; Thorburn, D.R.; Christodoulou, J. Clinical Spectrum and Functional Consequences Associated with Bi-Allelic Pathogenic PNPT1 Variants. J. Clin. Med. 2019, 8, 2020. https://doi.org/10.3390/jcm8112020

AMA Style

Rius R, Van Bergen NJ, Compton AG, Riley LG, Kava MP, Balasubramaniam S, Amor DJ, Fanjul-Fernandez M, Cowley MJ, Fahey MC, Koenig MK, Enns GM, Sadedin S, Wilson MJ, Tan TY, Thorburn DR, Christodoulou J. Clinical Spectrum and Functional Consequences Associated with Bi-Allelic Pathogenic PNPT1 Variants. Journal of Clinical Medicine. 2019; 8(11):2020. https://doi.org/10.3390/jcm8112020

Chicago/Turabian Style

Rius, Rocio, Nicole J. Van Bergen, Alison G. Compton, Lisa G. Riley, Maina P. Kava, Shanti Balasubramaniam, David J. Amor, Miriam Fanjul-Fernandez, Mark J. Cowley, Michael C. Fahey, Mary K. Koenig, Gregory M. Enns, Simon Sadedin, Meredith J. Wilson, Tiong Y. Tan, David R. Thorburn, and John Christodoulou. 2019. "Clinical Spectrum and Functional Consequences Associated with Bi-Allelic Pathogenic PNPT1 Variants" Journal of Clinical Medicine 8, no. 11: 2020. https://doi.org/10.3390/jcm8112020

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