Aortic Calcification in a Patient with a Gain-of-Function STAT1 Mutation

Smyth, Anna E.; Kaleviste, Epp; Snow, Aisling; Kisand, Kai; McMahon, Colin J.; Cant, Andrew J.; Leahy, T. Ronan

doi:10.1007/s10875-018-0513-z

Cited by 17 publications

(21 citation statements)

References 6 publications

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“…Specifically, Stat1 overexpression upregulated Runx2 expression and exacerbated osteogenic differentiation in VSMCs, whereas Stat1 inhibition decreased calcium content and calcification. Our results were consistent with the recent report by Smyth et al 26 that a gain-of-function mutation in the Stat1 gene lead to aortic calcification in a patient. Interestingly, we further identified a potential Stat1 recognition motif (5′-TCTCCAGTAAT-3′) for Stat1mediated activation of the RUNX2 promoter using PROMO and JASPAR databases.…”

Section: Discussionsupporting

confidence: 94%

Loss of PARP-1 attenuates diabetic arteriosclerotic calcification via Stat1/Runx2 axis

Wang

Liu

et al. 2020

Cell Death Dis

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Accelerated atherosclerotic calcification is responsible for plaque burden, especially in diabetes. The regulatory mechanism for atherosclerotic calcification in diabetes is poorly characterized. Here we show that deletion of PARP-1, a main enzyme in diverse metabolic complications, attenuates diabetic atherosclerotic calcification and decreases vessel stiffening in mice through Runx2 suppression. Specifically, PARP-1 deficiency reduces diabetic arteriosclerotic calcification by regulating Stat1-mediated synthetic phenotype switching of vascular smooth muscle cells and macrophage polarization. Meanwhile, both vascular smooth muscle cells and macrophages manifested osteogenic differentiation in osteogenic media, which was attenuated by PARP-1/Stat1 inhibition. Notably, Stat1 acts as a positive transcription factor by directly binding to the promoter of Runx2 and promoting atherosclerotic calcification in diabetes. Our results identify a new function of PARP-1, in which metabolism disturbance-related stimuli activate the Runx2 expression mediated by Stat1 transcription to facilitate diabetic arteriosclerotic calcification. PARP-1 inhibition may therefore represent a useful therapy for this challenging complication.

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Section: Discussionsupporting

confidence: 94%

Loss of PARP-1 attenuates diabetic arteriosclerotic calcification via Stat1/Runx2 axis

Wang

Liu

et al. 2020

Cell Death Dis

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“…In contrast to these reports, two adult patients with severe dermatophytosis and disseminated coccidioidomycosis due to STAT1 GOF mutation were recently reported to fail to respond to ruxolitinib [46]. In our study, one of the patients was treated with ruxolitinib, 10 mg twice daily, due to aortic calcification which is believed to be driven by IFN [20]. After 11 months of treatment, the in vivo ISG signature was erased according to gene expression analysis, but the calcification had still progressed slightly, and intermittent oral candidiasis was still occurring.…”

Section: Discussioncontrasting

confidence: 63%

“…Nevertheless, their excessive production potentiates several pathologies including vascular abnormalities [35] and systemic and organ-specific autoimmunity [17,36]. It has been noted that STAT1 GOF mutations and monogenic interferonopathies occasionally share certain phenotypic features such as intravascular calcifications [16,20] and SLE-like disease [1,17] that has provoked an idea that STAT1 GOF could be classified as a type I interferonopathy [37]. After the stimulation of STAT1 GOF cells with IFNs in vitro, ISGs are induced to a significantly higher extent than in control cells [37].…”

Section: Discussionmentioning

confidence: 99%

“…Patient details are given in Supporting Information Table . The clinical and laboratory parameters of two patients have been published before . Experiments were conducted on fresh whole blood, plasma and PBMCs.…”

Section: Methodsmentioning

confidence: 99%

“…In these conditions, circulating IFN‐α levels are increased and circulating blood cells reveal an IFN signature reflected by the upregulation of interferon‐stimulated genes (ISGs) . The shared characteristics between interferonopathies and STAT1 GOF include calcifications in the blood vessels and SLE‐like disease . IFNs have been implicated also in the pathogenesis of other autoimmune diseases that affect GOF STAT1 patients: type I diabetes , alopecia and thyroid disease .…”

Section: Introductionmentioning

confidence: 99%

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Interferon signature in patients with STAT1 gain‐of‐function mutation is epigenetically determined

et al. 2019

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STAT1 gain‐of‐function (GOF) variants lead to defective Th17 cell development and chronic mucocutaneous candidiasis (CMC), but frequently also to autoimmunity. Stimulation of cells with STAT1 inducing cytokines like interferons (IFN) result in hyperphosphorylation and delayed dephosphorylation of GOF STAT1. However, the mechanism how the delayed dephosphorylation exactly causes the increased expression of STAT1‐dependent genes, and how the intracellular signal transduction from cytokine receptors is affected, remains unknown. In this study we show that the circulating levels of IFN‐α were not persistently elevated in STAT1 GOF patients. Nevertheless, the expression of interferon signature genes was evident even in the patient with low or undetectable serum IFN‐α levels. Chromatin immunoprecipitation (ChIP) experiments revealed that the active chromatin mark trimethylation of lysine 4 of histone 3 (H3K4me3), was significantly enriched in areas associated with interferon‐stimulated genes in STAT1 GOF cells in comparison to cells from healthy donors. This suggests that the chromatin binding of GOF STAT1 variant promotes epigenetic changes compatible with higher gene expression and elevated reactivity to type I interferons, and possibly predisposes for interferon‐related autoimmunity. The results also suggest that epigenetic rewiring may be responsible for treatment failure of Janus kinase 1/2 (JAK1/2) inhibitors in certain patients.

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Novel Gain-of-Function Mutation in Stat1 Sumoylation Site Leads to CMC/CID Phenotype Responsive to Ruxolitinib

Gilmour

Gothe

et al. 2019

J Clin Immunol

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Aortic Calcification in a Patient with a Gain-of-Function STAT1 Mutation

Cited by 17 publications

References 6 publications

Loss of PARP-1 attenuates diabetic arteriosclerotic calcification via Stat1/Runx2 axis

Loss of PARP-1 attenuates diabetic arteriosclerotic calcification via Stat1/Runx2 axis

Interferon signature in patients with STAT1 gain‐of‐function mutation is epigenetically determined

Novel Gain-of-Function Mutation in Stat1 Sumoylation Site Leads to CMC/CID Phenotype Responsive to Ruxolitinib

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