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

TitleClinical Spectrum and Functional Consequences Associated with Bi-Allelic Pathogenic Variants.
Publication TypeJournal Article
Year of Publication2019
AuthorsRius, 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
JournalJ Clin Med
Date Published2019 Nov 19

(PNPase-polynucleotide phosphorylase) is involved in multiple RNA processing functions in the mitochondria. Bi-allelic pathogenic 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 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 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 variants that may guide management and further efforts into understanding the pathophysiological mechanisms for therapeutic development.

Alternate JournalJ Clin Med
PubMed ID31752325
Grant List111353 / / NHMRC Targeted Call for Research grant /
1155244 / / NHMRC research fellowship /
HG008900 / / National Human Genome Research Institute, the National Eye Institute, and the National Heart, Lung and Blood Institute grant /
HG009141 / / National Human Genome Research Institute grantR01 /