Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production

Brehm, Anja; Liu, Yin; Sheikh, Afzal; Marrero, Bernadette; Omoyinmi, Ebun; Zhou, Qing; Montealegre, Gina; Biancotto, Angélique; Reinhardt, Adam; Jesús, Adriana Almeida de; Pelletier, Martin; Tsai, Wanxia Li; Remmers, Elaine F.; Kardava, Lela; Hill, Suvimol; Kim, Susan; Lachmann, HJ; Mégarbané, André; Chae, Jae Jin; Brady, Jilian; Castillo, Rhina D.; Brown, Diane E.; Casaño, Ángel Vera; Gao, Ling; Chapelle, Dawn; Huang, Yan; Stone, Deborah L.; Chen, Yongqing; Sotzny, Franziska; Lee, Chyi‐Chia Richard; Kastner, Daniel L.; Torrelo, Antonio; Zlotogorski, Abraham; Moir, Susan; Gadina, Massimo; McCoy, Philip; Wesley, Robert; Rother, Kristina I.; Hildebrand, Peter W.; Brogan, Paul A.; Krüger, Elke; Aksentijevich, Ivona; Goldbach‐Mansky, Raphaela

doi:10.1172/jci81260

Cited by 265 publications

(262 citation statements)

References 45 publications

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“…This finding could support the hypothesis of a possible digenic or polygenic inheritance, as recently observed in other autoinflammatory conditions 14. Whole exome sequencing approach is currently ongoing in the Sardinian patient presenting with a complete clinical and functional DADA2 phenotype, with the aim to identify other genes that may affect the ADA2 enzymatic activity.…”

Section: Discussionsupporting

confidence: 83%

ADA2 deficiency (DADA2) as an unrecognised cause of early onset polyarteritis nodosa and stroke: a multicentre national study

et al. 2017

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DADA2 accounts for paediatric patients diagnosed with PAN-like disease and strokes and might explain an unrecognised condition in patients followed by adult rheumatologist. Timely diagnosis and treatment with anti-TNF agents are crucial for the prevention of severe complications of the disease. Functional assay to measure ADA2 activity should complement genetic testing in patients with non-confirming genotypes.

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Section: Discussionsupporting

confidence: 83%

ADA2 deficiency (DADA2) as an unrecognised cause of early onset polyarteritis nodosa and stroke: a multicentre national study

et al. 2017

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“…In addition to mutations in PSMB8 [3, 12–14, 16] in CANDLE/PRAAS, we described loss-of-function mutations in other proteasome subunits ( PSMB9 , PSMB4 , PSMA3 ) and the proteasome assembly protein, POMP , with expansion of the inheritance to compound heterozygous (mutations in PSMB4 ), digenic recessive (combinations of PSMA3, PSMB4 and/or PSMB9 ), and autosomal dominant (AD) ( POMP ) [17]. CANDLE is a rare disease with less than 100 cases described worldwide.…”

Section: Clinical and Pathogenic Description Of The Mendelian (Monogementioning

confidence: 99%

“…Knockdown experiments in healthy fibroblasts identified a critical threshold of proteasome dysfunction that leads to induction of type I IFN gene transcription. Proteasome dysfunction induced in wild-type cells by proteasome inhibitors results in dose-dependent increases in IFNA and IFNB transcription [17]. Although the exact mechanism leading to IFN transcription in CANDLE/PRAAS remains unknown, the type I IFN induction is independent of STING (stimulator of IFN genes protein) and MAVS (mitochondrial antiviral signaling protein), adaptors of RNA and DNA viral sensors, respectively [17].…”

Section: Clinical and Pathogenic Description Of The Mendelian (Monogementioning

confidence: 99%

“…Proteasome dysfunction induced in wild-type cells by proteasome inhibitors results in dose-dependent increases in IFNA and IFNB transcription [17]. Although the exact mechanism leading to IFN transcription in CANDLE/PRAAS remains unknown, the type I IFN induction is independent of STING (stimulator of IFN genes protein) and MAVS (mitochondrial antiviral signaling protein), adaptors of RNA and DNA viral sensors, respectively [17]. Patient cells are hyper-responsive to IFN γ [3] and IFNα (unpublished) stimulation and respond with increased STAT-1 phosphorylation; environmental stressors such as infections can trigger clinical flares [25].…”

Section: Clinical and Pathogenic Description Of The Mendelian (Monogementioning

confidence: 99%

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Insights from Mendelian Interferonopathies: Comparison of CANDLE, SAVI with AGS, Monogenic Lupus

2016

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Autoinflammatory disorders are sterile inflammatory conditions characterized by episodes of early-onset fever and disease-specific patterns of organ inflammation. Recently, the discoveries of monogenic disorders with strong type I interferon (IFN) signatures caused by mutations in proteasome degradation and cytoplasmic RNA and DNA sensing pathways suggest a pathogenic role of IFNs in causing autoinflammatory phenotypes. The IFN response gene signature (IGS) has been associated with systemic lupus erythematosus (SLE) and other autoimmune diseases. In this review, we compare the clinical presentations and pathogenesis of two IFN-mediated autoinflammatory diseases, CANDLE and SAVI, with Aicardi Goutières syndrome (AGS) and monogenic forms of SLE (monoSLE) caused by loss-of-function mutations in complement 1 (C1q) or the DNA nucleases, DNASE1 and DNASE1L3. We outline differences in intracellular signaling pathways that fuel a pathologic type I IFN amplification cycle. While IFN amplification is caused by predominantly innate immune cell dysfunction in SAVI, CANDLE, and AGS, autoantibodies to modified RNA and DNA antigens interact with tissues and immune cells including neutrophils and contribute to IFN upregulation in some SLE patients including monoSLE, thus justifying a grouping of “autoinflammatory” and “autoimmune” interferonopathies. Understanding of the differences in the cellular sources and signaling pathways will guide new drug development and the use of emerging targeted therapies.

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“…Initially, all affected individuals with PRAAS/CANDLE were found to have biallellic mutations in PSMB8 , resulting in deficiency of proteasome subunit β 8 (PSMB8), leading to abnormal function of the immunoproteosome 22–24. However, more recently, a similar phenotype was also described in patients with loss of other proteasome subunits, respectively, due to the mutations in PSMA3 , PSMB4 and PSMB9 genes 25. Patients with PRAAS present with a constellation of signs and symptoms that include recurrent fevers, joint contractions with muscle atrophy, partial lipodystrophy, hepatomegaly and basal ganglia calcification.…”

Section: Expanding the Concept Of Autoinflammationmentioning

confidence: 73%

Autoinflammatory diseases: update on classification diagnosis and management

2016

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The spectrum of systemic autoinflammatory disorders broadens continually. In part, this is due to the more widespread application of massive parallel sequencing, helping with novel gene discovery in this and other areas of rare diseases. Some of the conditions that have been described fit neatly into a conventional idea of autoinflammation. Others, such as Interferon-mediated autoinflammatory diseases, are broadening the concept which we consider to be autoinflammatory disorders. There is also a widening of the clinical phenotypes associated with certain genetic mutations, as genetic testing is used more regularly and increasing numbers of patients are screened. It is also increasingly evident that both autoinflammatory and autoimmune problems are frequently seen as complications of primary immunodeficiency disorders.The aim of this review is to provide an update on some recently discovered conditions, and to discuss how these disorders help to define the concept of autoinflammation. The review will also cover recent discoveries in the biology of innate-immune mediated inflammation, and describe how this has provided the biological rationale for using anti-IL-1 therapies in the treatment of many such conditions. Finally, we discuss the importance of recognising somatic mutations as causes of autoinflammatory clinical phenotypes, and provide practical advice on how this could be tackled in everyday clinical practice.

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Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production

Cited by 265 publications

References 45 publications

ADA2 deficiency (DADA2) as an unrecognised cause of early onset polyarteritis nodosa and stroke: a multicentre national study

ADA2 deficiency (DADA2) as an unrecognised cause of early onset polyarteritis nodosa and stroke: a multicentre national study

Insights from Mendelian Interferonopathies: Comparison of CANDLE, SAVI with AGS, Monogenic Lupus

Autoinflammatory diseases: update on classification diagnosis and management

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