2022
DOI: 10.1681/asn.2022040477
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Clinical Implications of a New DDX58 Pathogenic Variant That Causes Lupus Nephritis due to RIG-I Hyperactivation

Abstract: Background:Lupus nephritis (LN) is one of the most severe complications of systemic lupus erythematosus, with heterogeneous phenotypes and different responses to therapy. Identifying genetic causes of LN can facilitate more individual treatment strategies.Methods:We performed whole-exome sequencing in a cohort of Chinese patients with LN, and identified variants of a disease-causing gene. Extensive biochemical, immunologic, and functional analyses assessed the impact of the variant on type I interferon (IFN) s… Show more

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Cited by 22 publications
(10 citation statements)
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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%
“…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%
“…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%
“…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%