Clinical Implications of a New DDX58 Pathogenic Variant That Causes Lupus Nephritis due to RIG-I Hyperactivation

Peng, Jiahui; Wang, Yusha; Han, Xu; Zhang, Changming; Chen, Xiang; Jin, Ying; Yang, Zhaohui; An, Yi; Zhang, Jiahui; Liu, Zhengzhao; Chen, Yinghua; Gao, Erzhi; Zhang, Yangyang; Xing, Feng; Chen, Zheng; Zhou, Qing; Liu, Zhihong

doi:10.1681/asn.2022040477

Cited by 12 publications

(8 citation statements)

References 35 publications

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“…Moreover, we demonstrate clear protection from cisplatin-induced injury by genetic ablation of only the mtRNA sensing pathway (RIG-I KO and MAVS KO mice) and that direct transfection of mtRNA is sufficient to induce inflammatory gene signatures that are detected in injured kidneys. Finally, we note that a hyperactivating variant of RIG-I was recently associated with kidney failure in lupus 36 . Thus, integrating unbiased transcriptomics and metabolomic data from cisplatin injury allowed us to identify a mechanism in which maintenance of renal NAD + levels prevents the release of mtRNA and activation of the RIG-I pathway, a prominent driver of inflammation that contributes to KD (Fig.…”

Section: Discussionmentioning

confidence: 72%

NAD+ precursor supplementation prevents mtRNA/RIG-I-dependent inflammation during kidney injury

et al. 2023

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Section: Discussionmentioning

confidence: 72%

NAD+ precursor supplementation prevents mtRNA/RIG-I-dependent inflammation during kidney injury

et al. 2023

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“…On the basis of the pathogenesis, initiation of JAK inhibitor therapy (baricitinib) showed certain clinical responses with effective suppression of the type I interferon signal. 33 For the patient with the HAVCR2 p.Y82C mutation, current multi-immunosuppressive drugs and rituximab showed no effect on controlling his proteinuria. Allogeneic hematopoietic stem cell transplant may be a promising treatment for this patient.…”

Section: Discussionmentioning

confidence: 99%

Pathogenic Gene Spectrum and Clinical Implication in Chinese Patients with Lupus Nephritis

Zhang

Han

Jin

et al. 2023

CJASN

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Background Lupus nephritis is a rare immunological disorder. Genetic factors are considered important in its causation. We aim to systematically investigate the rare pathogenic gene variants in patients with lupus nephritis. Methods Whole-exome sequencing was used to screen pathogenic gene variants in 1886 probands with lupus nephritis. Variants were interpreted on the basis of known pathogenic variants or the American College of Medical Genetics and Genomics guidelines and studied by functional analysis, including RNA sequencing, quantitative PCR, cytometric bead array, and Western blotting. Results Mendelian form of lupus nephritis was confirmed in 71 probands, involving 63 variants in 39 pathogenic genes. The detection yield was 4%. The pathogenic genes enriched in nuclear factor kappa-B (NF-κB), type I interferon, phosphatidylinositol-3-kinase/serine/threonine kinase Akt (PI3K/AKT), Ras GTPase/mitogen-activated protein kinase (RAS/MAPK), and Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways. Clinical manifestation patterns were diverse among different signaling pathways. More than 50% of the pathogenic gene variants were reported to be associated with lupus or lupus nephritis for the first time. The identified pathogenic gene variants of lupus nephritis overlapped with those of autoinflammatory and immunodeficiency diseases. Inflammatory signatures, such as cytokine levels of IL-6, IL-8, IL-1β, IFNα, IFNγ, and IP10 in serum and transcriptional levels of interferon-stimulated genes in blood, were significantly higher in patients with pathogenic gene variants compared with controls. The overall survival rate of patients with pathogenic gene variants was lower than those without pathogenic gene variants. Conclusions A small fraction of patients with lupus nephritis had identifiable pathogenic gene variants, primarily in NF-κB, type I interferon, PI3K/AKT, JAK/STAT, RAS/MAPK, and complement pathways.

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“…Transcriptome analysis revealed an increased IFN signature in patient monocytes. One patient was effectively treated with baricitinib[ 9 ]. Gain-of-function IFIH1 gene variants lead to an inadequate perception of both own and viral nucleic acids and contribute to the hyperactivation of the IFN-I type[ 10 ].…”

Section: Discussionmentioning

confidence: 99%

IFIH1 and DDX58 gene variants in pediatric rheumatic diseases

Raupov¹,

Suspitsin²,

Belozerov³

et al. 2023

World J Clin Pediatr

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BACKGROUND The IFIH1 gene codes the MDA5 protein and the DDX58 gene codes the RIG-I receptor. Both proteins are parts of the interferon (IFN) I signaling pathway and are responsible for antiviral defense and innate immune response. IFIH1 and DDX58 polymorphisms are associated with a spectrum of autoimmune diseases. Rare gain-of-function IFIH1 mutations have been found in Singleton-Merten and Aicardi-Goutières syndrome, while DDX58 mutation can cause atypical Singleton-Merten syndrome. AIM To characterize children with pediatric rheumatic diseases (PRD) carrying DDX58 or IFIH1 variants. METHODS Clinical exome sequencing was performed on 92 children with different PRD. IFIH1 and DDX58 variants have been detected in 14 children. IFN-I score has been analyzed and the clinical characteristics of patients have been studied. RESULTS A total of seven patients with systemic lupus erythematosus (SLE) ( n = 2), myelodysplastic syndrome with SLE features at the onset of the disease ( n = 1), mixed connective tissue disease (MCTD) ( n = 1), undifferentiated systemic autoinflammatory disease (uSAID) ( n = 3) have 5 different variants of the DDX58 gene. A common non-pathogenic variant p.D580E has been found in five children. A rare variant of uncertain significance (VUS) p.N354S was found in one patient with uSAID, a rare likely non-pathogenic variant p.E37K in one patient with uSAID, and a rare likely pathogenic variant p.Cys864fs in a patient with SLE. Elevated IFN-I score was detected in 6 of 7 patients with DDX58 variants. Seven patients had six different IFIH1 variants. They were presented with uSAID ( n = 2), juvenile dermatomyositis (JDM) ( n = 1), SLE-like disease ( n = 1), Periodic fever with aphthous stomatitis, pharyngitis, and adenitis syndrome ( n = 1), and systemic onset juvenile idiopathic arthritis ( n = 1). Three patients have VUS p.E627X, one patient has benign variant p.I923V. Rare VUS p.R595H was detected in the JDM patient. Another rare VUS p.L679Ifs*2 and previously not reported variant p.V599Ffs*5 were detected in the patient with uSAID. One patient with uSAID has rare VUS p.T520A. All patients had elevated IFN-I scores. CONCLUSION Rare compound-heterozygous IFIH1 variant (p.L679Ifs*2 and p.V599Ffs*5), heterozygous IFIH1 variant (p.T520A) and heterozygous DDX58 variant (p.Cys864fs) are probably disease causative for uSAID and SLE. The majority of patients with different DDX58 ...

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Clinical Implications of a New DDX58 Pathogenic Variant That Causes Lupus Nephritis due to RIG-I Hyperactivation

Cited by 12 publications

References 35 publications

NAD+ precursor supplementation prevents mtRNA/RIG-I-dependent inflammation during kidney injury

NAD+ precursor supplementation prevents mtRNA/RIG-I-dependent inflammation during kidney injury

Pathogenic Gene Spectrum and Clinical Implication in Chinese Patients with Lupus Nephritis

IFIH1 and DDX58 gene variants in pediatric rheumatic diseases

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