ArticleArthritis & rheumatology (Hoboken, N.J.)2018
Brief Report: Novel UNC13D Intronic Variant Disrupting an NF-κB Enhancer in a Patient With Recurrent Macrophage Activation Syndrome and Systemic Juvenile Idiopathic Arthritis.
Article in Arthritis & rheumatology (Hoboken, N.J.), 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 47 citations in OpenAlex.
- Case Report: Munc13-4 deficiency presenting with autoimmune neuropathy years before FLH: implications for early genetic screening and HSCT timing.Frontiers in immunology · 2026Article
- Hemophagocytic Lymphohistiocytosis Gene Variants in Severe COVID-19 Cytokine Storm Syndrome.Viruses · 2025Article
- UBE2D1 as a key biomarker in systemic juvenile idiopathic arthritis: a new perspective on diagnosis and disease activity assessment.Arthritis research & therapy · 2025Article
- Whole exome sequencing for identifying rare genetic variants related to idiopathic granulomatous mastitis.Clinical rheumatology · 2025Article
- Role of DOCK8 in cytokine storm syndromes.The Journal of allergy and clinical immunology · 2025Article
- Clinical and genetic analysis of macrophage activation syndrome complicating juvenile idiopathic inflammatory myopathies.Pediatric research · 2025Article
- New discoveries in the genetics and genomics of systemic juvenile idiopathic arthritis.Expert review of clinical immunology · 2024Review
- Functional categorization of gene regulatory variants that cause Mendelian conditions.Human genetics · 2024Review
- IL-1 Family Blockade in Cytokine Storm Syndromes.Advances in experimental medicine and biology · 2024Review
- Functional role of UNC13D in immune diseases and its therapeutic applications.Frontiers in immunology · 2024Review
- Genetics of Macrophage Activation Syndrome in Systemic Juvenile Idiopathic Arthritis.Advances in experimental medicine and biology · 2024Review
- CD8Advances in experimental medicine and biology · 2024Review
- Cytokine Storm Syndrome Associated with Systemic Juvenile Idiopathic Arthritis.Advances in experimental medicine and biology · 2024Review
- IL-18 Binding Protein-Producing Cells Attenuate Anemia in Murine Macrophage Activation Syndrome.Journal of immunology (Baltimore, Md. : 1950) · 2023Article
- The Multifaceted Immunology of Cytokine Storm Syndrome.Journal of immunology (Baltimore, Md. : 1950) · 2023Review
- Genetic Background and Molecular Mechanisms of Juvenile Idiopathic Arthritis.International journal of molecular sciences · 2023Review
- Whole exome sequencing in a juvenile idiopathic arthritis large family with SERPINA1 gene mutations.BMC rheumatology · 2022Article
- Hemophagocytic Lymphohistiocytosis Gene Variants in Multisystem Inflammatory Syndrome in Children.Biology · 2022Article
- COVID-19 and cytokine storm syndrome: are there lessons from macrophage activation syndrome?Translational research : the journal of laboratory and clinical medicine · 2021Review
- Review
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Authors and funding
8 authors at 4 institutions in 1 country.
Funding
Abstract
objectiveMacrophage activation syndrome (MAS) is a life-threatening complication of systemic juvenile idiopathic arthritis (JIA) and has pathologic similarity to hemophagocytic lymphohistiocytosis (HLH). Intronic variants in UNC13D are found in patients with familial HLH type 3 (FHLH3), but the role of noncoding variants in MAS is unknown. The objective of this study was to identify deep intronic UNC13D variants in patients with MAS.
methodsA custom enrichment library was constructed to sequence a genomic region of ~1 Mb flanking UNC13D in 24 patients with systemic JIA, recurrent MAS, and negative results of prior genetic (exon/coding) testing. The functional consequences of intronic variants were assessed using quantitative polymerase chain reaction in patient-derived peripheral blood mononuclear cells (PBMCs), electromobility shift assay, in vitro transcriptional enhancer assays, and natural killer (NK) cell degranulation assays.
resultsWe evaluated a patient with systemic JIA and recurrent MAS in whom a novel functional intronic variant in UNC13D, c.117+143A>G, was observed. This variant occurred in a proposed regulatory region that drives lymphocyte-specific UNC13D expression and is associated with reduced transcript levels in patient PBMCs. This variant also disrupted NF-κB binding to a functional transcriptional enhancer, leading to reduced enhancer activity in vitro. Partial knockdown of UNC13D expression also led to impaired NK cell degranulation. An additional patient was identified with a previously described UNC13D intronic variant, for a total noncoding variant hit rate of 8.3% (2 of 24).
conclusionThese findings highlight the notion that intronic variants in key regulatory regions may be associated with MAS in patients with systemic JIA and support deep sequencing approaches when causative coding variants are not identified.
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