Systemic inflammation and chronic kidney disease in a patient due to the RNASEH2B defect

Abstract

Introduction Aicardi-Goutières (AGS) is a rare immune dysregulated disease due to mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, or IFIH1. Clinical features include basal ganglia calcifications, white matter abnormalities, and cerebral atrophy. Severe systemic inflammation and chronic kidney disease (CKD) are extremely rare in AGS. Herein, we report a patient presenting with systemic inflammation and CKD to broaden the clinical phenotype spectrum of the RNASEH2B defect. Methods All testing and molecular genetic analysis were performed after obtaining the informed consent of the parents. Demographic, clinical, and laboratory findings were abstracted from outpatient and inpatient encounters. Cerebral magnetic resonance imaging (MRI), computed tomography (CT) scans, and renal biopsy histopathology reports were reviewed and summarized. Whole exome sequencing (WES) was performed on peripheral blood cells. After exposure to cGAMP in vitro for 24 h, mRNA expression of 12 IFN-stimulated cytokine genes in PBMCs was assessed. Serum cytokine levels were detected by Milliplex. Results A 11-year-old girl presented with recurrent aseptic fever, arthritis, chilblains, failure to thrive, mild hearing loss, and neurological manifestations. Laboratory and immunologic findings demonstrated lymphopenia, low complement levels, positive autoantibodies, elevated levels of acute-phase reactants and inflammatory cytokines. Cerebral imaging showed cerebral atrophy, white matter abnormalities, and intracranial calcification. Renal biopsy showed glomerular sclerosis in 3 of 14 glomeruli, infiltration of lymphocytes and other mononuclear cells. WES revealed a homozygous and heterozygous mutations in RNASEH2B. Over-expression of IFN-stimulated cytokine genes was observed, including IFI44, IFI27, IFIT1, IFIT2, IFIT3, ISG15, OAS1, and SIGLEC1. Conclusions To date, only two cases with AGS have been reported to have renal disease. Here, we describe a patient with both homozygous and heterozygous variants in RNASEH2B, presenting with neurological manifestations, persistently systemic autoinflammation, and CKD. CKD has never been reported in patients with AGS due to the RNASEH2B defect. Trial registration Not applicable; this was a retrospective study.

DNA damage contributes to neurotoxic inflammation in Aicardi-Goutières syndrome astrocytes

“…Our data suggest that type I IFN pathways may not be the major driver of disease in AGS with a relevant contribution of DNA damage-associated apoptotic and proinflammatory responses. In agreement, both TREX1 and RNASEH2B deficiencies have been clinically associated with inflammatory symptoms such as inflammatory myopathy ( Tumiene et al, 2017 ) and systemic inflammation ( He et al, 2021 ). Although links between JAK-STAT signaling, type I IFN induction, and neurotoxicity warrant further investigation in our experimental system through pharmacological inhibitors such as ruxolitinib, IFNα receptor blocking antibodies, or genetic modifications of key players, our observations are in line with a recent report in which type I IFN–independent genomic instability was shown to cause AGS-like cell toxicity in a murine model of neural Rnaseh2b inactivation ( Aditi et al, 2021 ).…”

Whole-Exome Sequencing in Family Trios Reveals De Novo Mutations Associated with Type 1 Diabetes Mellitus

“…Given that TDG enzyme control activates DNA demethylation, TDG gene expression was significantly upregulated in the IFN-α–treated islets and lymphocyte cells [ 66 ]. The RNASEH2B gene located in 13q14.3 is involved in the activation of the interferon pathway, leading to the infiltration of lymphocytes and mononuclear cells, and local chronic inflammation [ 67 ]. The TYRO3 gene located in 15q15.1 regulates immunoregulation, plays an important role in the inhibition of the Toll-like-receptor-mediated innate immune response, and is an essential regulator of immune homeostasis [ 68 , 69 ].…”

Behçet syndrome: The disturbed balance between anti- (CLEC12A, CLC) and pro-inflammatory (IFI27) gene expressions

“…37,38 The literature harbors many inflammatory/immunological conditions including inflammatory bowel diseases, psoriasis, systemic lupus erythematosus, Sjögren's syndrome, antiphospholipid syndrome, acute graft-versus-host disease, immune thrombocytopenic purpura, Aicardi-Goutieres syndrome, Kikuchi-Fujimoto, and hand, foot, and mouth diseases, in which significant increases inIFI27 expression have been reported. [39][40][41][42][43][44][45][46][47][48][49][50] It is also well-known that, some of these above-mentioned inflammatory diseases (i.e., inflammatory bowel diseases, psoriasis, and systemic lupus erythematosus) have an intersection with BS. [51][52][53] Similar to CLEC12A , IFI27 is also among the top 10 most differentially ex-pressed genes of the class comparisons (second in M vs. C with an FC: 3.49, second in Ovs.…”