Clinical Spectrum and Functional Consequences Associated with Bi-Allelic Pathogenic PNPT1 Variants
| العنوان: | Clinical Spectrum and Functional Consequences Associated with Bi-Allelic Pathogenic PNPT1 Variants |
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| المؤلفون: | Michael C Fahey, David J. Amor, John Christodoulou, Maina P. Kava, Rocio Rius, Mary Kay Koenig, Shanti Balasubramaniam, Gregory M. Enns, Lisa G. Riley, Alison G. Compton, Tiong Yang Tan, Mark J. Cowley, Miriam Fanjul-Fernández, Nicole J Van Bergen, Simon Sadedin, David R. Thorburn, Meredith Wilson |
| المصدر: | Journal of Clinical Medicine, Vol 8, Iss 11, p 2020 (2019) Journal of Clinical Medicine; Volume 8; Issue 11; Pages: 2020 |
| بيانات النشر: | MDPI AG, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | respiratory chain, Respiratory chain, lcsh:Medicine, splice defect, medicine.disease_cause, mitochondrial, PNPT1, PNPase, interferon, OXPHOS, mutation, 03 medical and health sciences, 0302 clinical medicine, medicine, Allele, oxphos, 030304 developmental biology, Genetics, 0303 health sciences, Mutation, Innate immune system, business.industry, lcsh:R, Respiratory chain complex, General Medicine, Phenotype, 3. Good health, pnpase, RNA splicing, pnpt1, business, 030217 neurology & neurosurgery, Function (biology) |
| الوصف: | 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. |
| وصف الملف: | application/pdf |
| تدمد: | 2077-0383 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3fd4eb08fbb6a52f77bc62ebe708ed04Test https://doi.org/10.3390/jcm8112020Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....3fd4eb08fbb6a52f77bc62ebe708ed04 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20770383 |
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