Heterogeneity of PNPT1 neuroimaging: mitochondriopathy, interferonopathy or both?

Abstract

BackgroundBiallelic variants in PNPT1 cause a mitochondrial disease of variable severity. PNPT1 (polynucleotide phosphorylase) is a mitochondrial protein involved in RNA processing where it has a dual role in the import of small RNAs into mitochondria and in preventing the formation and release of mitochondrial double-stranded RNA into the cytoplasm. This, in turn, prevents the activation of type I interferon response. Detailed neuroimaging findings in PNPT1-related disease are lacking with only a few patients reported with basal ganglia lesions (Leigh syndrome) or non-specific signs.Objective and methodsTo document neuroimaging data in six patients with PNPT1 highlighting novel findings.ResultsTwo patients exhibited striatal lesions compatible with Leigh syndrome; one patient exhibited leukoencephalopathy and one patient had a normal brain MRI. Interestingly, two unrelated patients exhibited cystic leukoencephalopathy resembling RNASET2-deficient patients, patients with Aicardi-Goutières syndrome (AGS) or congenital CMV infection.ConclusionWe suggest that similar to RNASET2, PNPT1 be searched for in the setting of cystic leukoencephalopathy. These findings are in line with activation of type I interferon response observed in AGS, PNPT1 and RNASET2 deficiencies, suggesting a common pathophysiological pathway and linking mitochondrial diseases, interferonopathies and immune dysregulations.

Genomics of perivascular space burden unravels early mechanisms of cerebral small vessel disease

“…The enrichment was even stronger (30-fold) when focusing on WM PVS loci only, comprising several genes involved in early onset leukodystrophies (monogenic disorders with selective and primary involvement of the brain white matter): 42 GFAP (chr17q21.31), mutations of which cause Alexander disease, a rare neurodegenerative disorder of astrocytes leading to psychomotor regression and death; 43 SLC13A3 (chr20q13.12), causing acute reversible leukoencephalopathy with increased urinary alpha-ketoglutarate; 44 and PNPT1 (chr2p16.1), causing Aicardi-Goutières syndrome and cystic leukoencephalopathy (Figure 4). 45,46 Although several genes near PVS lead risk variants were described to be involved in glioma (TMEM212, NBEAL1, LPAR1, WNT7A, ITGB5, EFEMP1, LAMC1, OPA1, CALD1, and ISYNA1) we found no signi cant enrichment for glioma genes from the COSMIC catalogue. 41 To seek evidence for a causal implication of speci c genes and variants in observed associations, we performed transcriptome-wide association studies (TWAS) using TWAS-Fusion, 47 with European PVS GWAS summary statistics and the GTEX v7 multi-tissue (RNA-seq) database, focusing on brain, vascular and blood tissues.…”

Mitochondrial Nucleic Acid as a Driver of Pathogenic Type I Interferon Induction in Mendelian Disease

“…described loss of the mtRNA exoribonuclease PNPT1 to result in an accumulation and cytosolic leakage of dsRNA derived from bidirectional mtDNA transcription, triggering IFN through a BAX/BAK-dependent mechanism ( 76 ). Consistent with the type I interferonopathy disease spectrum, patients carrying hypomorphic mutations in PNPT1 display enhanced IFN signaling in blood (and, in some cases, intracerebral calcification, a well-known clinical feature of IFN activation) ( 76 , 78 ). Mutations in NGLY1 , encoding conserved deglycosylation enzyme NGLY1, cause a severe neurodevelopmental phenotype ( 79 , 80 ).…”

“…Further indication of a possible relationship between mitochondrial disease and the type I interferonopathies comes from shared clinical features, such as intracranial calcification being an established sign in both settings ( 3 , 118 ). Similarly, bilateral striatal necrosis is recurrent in mitochondrial disease, and consistently described in the context of mutations in both PNPT1 ( 78 ) and the type I interferonopathy due to ADAR1 loss-of-function ( 119 ). Likewise, dystonia, peripheral neuropathy, hypertrophic cardiomyopathy and isolated spastic paraparesis, recorded in patients with mutations in ATAD3A ( 77 , 84 , 85 ), are features of interferon-related disease ( 120 , 121 ).…”

“…Interestingly, hypomorphic mutations in RNASET2 and TRNT1 may also be associated with perturbed mtNA homeostasis leading to enhanced IFN signaling ( 91 , 92 ). Mutations in RNASET2 cause a phenotype mimicking congenital viral infection, reminiscent of some type I interferonopathies ( 78 , 93 ), and RNASET2 has been suggested to play a role in mitochondrial ribosomal RNA degradation in the IMS ( 94 ). Further, IFN pathway induction has been observed in some patients with mutations in TRNT1 ( 91 ), and TRNT1 is required for tRNA aminoacylation of mitochondrial and cytosolic tRNA, with protein dysfunction leading to defective mitochondrial translation ( 95 ).…”

Mitochondrial RNA, a new trigger of the innate immune system

“…Based on a literature, 29 patients with biallelic mutations in PNPase gene were identified. This group of patients represent distinct phenotypes, associated with simultaneous abnormality in various organs (Table 1) (Alodaib et al, 2016; Bamborschke et al, 2021; Dhir et al, 2018; Eaton et al, 2018; Hosseini Bereshneh et al, 2021; Matilainen et al, 2017; Pennisi et al, 2020; Rius et al, 2019; Sato et al, 2018; Slavotinek et al, 2015; Vedrenne et al, 2012; von Ameln et al, 2012). Consequently, correlating AGS with a spectrum of syndromes that are observed in patients with PNPase mutations can be problematic.…”