Inspired by a patient
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.
Matilainen S, Carroll CJ, Richter U, Euro L, Pohjanpelto M, Paetau A, Isohanni P, Suomalainen A. Defective mitochondrial RNA processing due to PNPT1 variants causes Leigh syndrome. Hum Mol Genet. 2017 Sep 1;26(17):3352-3361. doi: 10.1093/hmg/ddx221. PMID: 28645153.
Abstract
Leigh syndrome is a severe infantile encephalopathy with an exceptionally variable genetic background. We studied the exome of a child manifesting with Leigh syndrome at one month of age and progressing to death by the age of 2.4 years, and identified novel compound heterozygous variants in PNPT1, encoding the polynucleotide phosphorylase (PNPase). Expression of the wild type PNPT1 in the subject's myoblasts functionally complemented the defects, and the pathogenicity was further supported by structural predictions and protein and RNA analyses. PNPase is a key enzyme in mitochondrial RNA metabolism, with suggested roles in mitochondrial RNA import and degradation. The variants were predicted to locate in the PNPase active site and disturb the RNA processing activity of the enzyme. The PNPase trimer formation was not affected, but specific RNA processing intermediates derived from mitochondrial transcripts of the ND6 subunit of Complex I, as well as small mRNA fragments, accumulated in the subject's myoblasts. Mitochondrial RNA processing mediated by the degradosome consisting of hSUV3 and PNPase is poorly characterized, and controversy on the role and location of PNPase within human mitochondria exists. Our evidence indicates that PNPase activity is essential for the correct maturation of the ND6 transcripts, and likely for the efficient removal of degradation intermediates. Loss of its activity will result in combined respiratory chain deficiency, and a classic respiratory chain-deficiency-associated disease, Leigh syndrome, indicating an essential role for the enzyme for normal function of the mitochondrial respiratory chain.
Bamborschke D, Kreutzer M, Koy A, Koerber F, Lucas N, Huenseler C, Herkenrath P, Lee-Kirsch MA, Cirak S. PNPT1 mutations may cause Aicardi-Goutières-Syndrome. Brain Dev. 2021 Feb;43(2):320-324. doi: 10.1016/j.braindev.2020.10.005. Epub 2020 Nov 4. PMID: 33158637.
Abstract
Background: Aicardi-Goutières syndrome (AGS) is a clinically and genetically heterogenous autoinflammatory disorder caused by constitutive activation of the type I interferon axis. It has been associated with the genes TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, IFIH1. The clinical diagnosis of AGS is usually made in the context of early-onset encephalopathy in combination with basal ganglia calcification or white matter abnormalities on cranial MRI and laboratory prove of interferon I activation.
Case presentation: We report a patient with early-onset encephalopathy, severe neurodevelopmental regression, progressive secondary microcephaly, epilepsy, movement disorder, and white matter hyperintensities on T2 weighted MRI images. Via whole-exome sequencing, we identified a novel homozygous missense variant (c.1399C > T, p.Pro467Ser) in PNPT1 (NM_033109). Longitudinal assessment of the interferon signature showed a massively elevated interferon score and chronic type I interferon-mediated autoinflammation.
Conclusion: Bi-allelic mutations in PNPT1 have been reported in early-onset encephalopathy. Insufficient nuclear RNA import into mitochondria with consecutive disruption of the respiratory chain was proposed as the main underlying pathomechanism. Recent studies have shown that PNPT1 deficiency causes an accumulation of double-stranded mtRNAs in the cytoplasm, leading to aberrant type I interferon activation, however, longitudinal assessment has been lacking. Here, we present a case of AGS with continuously elevated type I interferon signature with a novel likely-pathogenic homozygous PNTP1 variant. We highlight the clinical value of assessing the interferon signature in children with encephalopathy of unknown origin and suggest all patients presenting with a phenotype of AGS should be screened for mutations in PNPT1.
Reigada S, Santos C, Ramos F, Carvalho S, Ribeiro J, Cancelinha C, Diogo L. Combined Oxidative Phosphorylation Deficiency Type-13 with Perinatal Presentation: A Case Report. Endocr Metab Immune Disord Drug Targets. 2023 Oct 11. doi: 10.2174/0118715303274239231005105248. Epub ahead of print. PMID: 37861028.
Abstract
Introduction: Polynucleotide phosphorylase is involved in RNA processing in mitochondria. Biallelic variants in PNPT1 cause mitochondrial RNA import protein deficiency and heterogeneous clinical manifestations.
Case report: The patiest was the first child of remote consanguineous parents, born at 35 weeks by caesarean section due to fetal growth restriction. Apgar index was 9/10/10. Birth weight, length and head circumference were at 3rd, <3rd and 10th percentiles, respectively. In the first hours of life, respiratory distress, hypoglycaemia and seizures ensued. She started invasive mechanic ventilation, phenobarbital and was transferred to ICU. Physical examination showed minor facial dysmorphisms, brief eye-opening, hypotonia and hyporeflexia. Electroencephalogram showed immature pattern and multifocal paroxysmal activity. MRI at D8 of life showed severe reduced brain volume. Normal aminoacid screen was also observed. Expanded newborn screening was negative. Mitochondrial organic aciduria was seen. WES showed a homozygotic likely pathogenic variant in the PNPT1 gene. MRI at 6-months showed brain atrophy, thin corpus callosum, reduced brainstem volume. Bilateral and symmetrical lesions in globi pallidi, compatible with Leigh síndrome were observed. Currently, at 14 months, no neurodevelopment progress, dystonia, visual deficit, sensorineural deafness, hypertrophic cardiomyopathy and microcephaly are observed.
Conclusion: The early and severe Leigh-like presentation of our patient expands the phenotype spectrum of this disease. As far as we know, this is the first reported case of PNPT1 mutation with onset in the perinatal period. Moreover, hypertrophic cardiomyopathy has not yet been described in association with mutation of the PNPT1 gene. WES was the key for early diagnosis in this patient. It should be done in all children with severe clinical presentation of unknown origin.
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