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-Fernandez; Mark J Cowley; Michael C Fahey; Mary K Koenig; Gregory M Enns; Simon Sadedin; Meredith J Wilson; Tiong Y Tan; David R Thorburn; John Christodoulou

doi:10.3390/jcm8112020

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

J Clin Med. 2019 Nov 19;8(11):2020. doi: 10.3390/jcm8112020.

Authors

Rocio Rius^{1

2}, Nicole J Van Bergen^{1

2}, Alison G Compton^{1

2}, Lisa G Riley^{3

4}, Maina P Kava^{5

6}, Shanti Balasubramaniam^{6

7

8}, David J Amor^{1

2

9}, Miriam Fanjul-Fernandez^{2

9}, Mark J Cowley^{10

11

12}, Michael C Fahey¹³, Mary K Koenig¹⁴, Gregory M Enns¹⁵, Simon Sadedin^{1

9}, Meredith J Wilson^{16

17}, Tiong Y Tan^{1

2

9}, David R Thorburn^{1

2

9}, John Christodoulou^{1

2

4

9}

Affiliations

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.

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.

Keywords: OXPHOS; PNPT1; PNPase; interferon; mitochondrial; mutation; respiratory chain; splice defect.

Abstract

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