Novel interferonopathies associated with mutations in RIG-I like receptors

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Cytokine & Growth Factor Reviews xxx (2015) xxx–xxx

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Novel interferonopathies associated with mutations in RIG-I like receptors Insa Buers, Yvonne Nitschke, Frank Rutsch* Department of General Pediatrics, Muenster University Children’s Hospital, Albert-Schweitzer-Campus 1, Building A1, 48149 Muenster, Germany

A R T I C L E I N F O

A B S T R A C T

Article history: Available online xxx

Type I interferonopathies are a relatively new class of inherited autoimmune disorders associated with an inborn elevated interferon response. Activation of cytosolic receptors which recognize viral double stranded RNA including the RIG-I (retinoic acid–inducible gene I) like receptors RIG-I and MDA5 (melanoma differentiation-associated gene 5) has been shown to induce the transcription of type I interferon genes. Within recent years, with the help of next generation sequencing techniques in syndromic families, mutations in the genes encoding for RIG-I and MDA5 have been identified to cause rare diseases including Aicardi-Goutières syndrome, Systemic Lupus Erythematosus in certain individuals as well as classic and atypical Singleton-Merten syndrome. Patients carrying mono-allelic mutations in MDA5 and RIG-I show constitutive activation of the RIG-I receptors and downstream signalling associated with increased type I interferon production. Although differing in the degree of phenotypic expression and severity, the phenotype of these “novel” diseases shows a considerable overlap reflecting their common pathogenetic pathway. ã 2016 Elsevier Ltd. All rights reserved.

Keywords: Singleton-Merten Aicardi-Goutières SLE

Contents 1.

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Introduction . . . . . . . . . . . . . . . . . . . . Singleton-Merten syndrome . . 1.1. Systemic Lupus Erythematosus 1.2. Aicardi-Goutières-syndrome . . 1.3. Conclusion . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . .

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1. Introduction Type I interferons (IFN) belong to the cytokine family with antiviral function and are involved in regulatory effects on the immune response [1,2]. Secreted type I IFN proteins are synthesised by almost all cell types and mediate immune response by binding to the type I IFN receptor composed of the two chains: IFNAR1 and IFNAR2 [3]. Studies in rats in the early 80’s of the last century suggested that elevated IFN levels are detrimental for the

* Corresponding author. E-mail addresses: [email protected] (I. Buers), [email protected] (Y. Nitschke), [email protected] (F. Rutsch).

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mammalian organism [4]. In 1988, Pierre Lebon and colleagues detected high levels of IFN in the cerebrospinal fluid (CSF) from patients with Aicardi-Goutières syndrome (AGS), a rare autoimmune disorder [5]. Within recent years, in the advent of whole genome analysis mutations in different steps of intracellular signaling leading to IFN production have been discovered to be associated with this rare syndrome and others. Accordingly, in 2011 Crow et al. [6] suggested to term Mendelian disorders associated with elevated IFN response as “interferonopathies”. The most frequent trigger of type I IFN synthesis is the activation of cytosolic receptors which recognize viral double stranded RNA (dsRNA) [7]. The most common receptors for the induction of type I IFN signaling are the RIG-I (retinoic acid– inducible gene I) like receptors RIG-I and MDA5 (melanoma

http://dx.doi.org/10.1016/j.cytogfr.2016.03.005 1359-6101/ ã 2016 Elsevier Ltd. All rights reserved.

Please cite this article in press as: I. Buers, et al., Novel interferonopathies associated with mutations in RIG-I like receptors, Cytokine Growth Factor Rev (2016), http://dx.doi.org/10.1016/j.cytogfr.2016.03.005

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differentiation-associated gene 5). These receptors induce the transcription of type I IFN genes via mitochondrial antiviral signaling proteins (MAVS) followed by the NF-kB (nuclear factor kappa-light-chain-enhancer of activated B cells), IRF3 (interferon regulatory factor 3), and AP-1 (activator protein 1) signaling pathway [7]. A couple of studies associate polymorphisms in the genes encoding for RIG-I like receptors with several autoimmune diseases. These include autoimmune diseases such as multiple sclerosis, diabetes mellitus type 1, psoriatic arthritis, cutaneous psoriasis and dermatomyositis [8–12]. Although these association studies support a link between autoimmune diseases and the RIG-I like receptors, direct evidence linking monogenetic disorders with mutations in RIG-I like receptors was missing. However, in the last two years, several groups identified gain-of-function mutations in the RIG-I like receptor genes IFIH1 (interferon induced with helicase C domain 1) or DDX58 (DEAD box polypeptide 58) as disease causing for Singleton-Merten syndrome (SMS), Systemic Lupus Erythematosus (SLE) or AGS [13–16]. Accordingly, individuals with these diseases show elevated expression of IFN related genes. The identification of the genetic cause of these rare autoimmune diseases with inadequate levels of type I IFN shed new light into the disease causing mechanisms of interferonopathies. 1.1. Singleton-Merten syndrome SMS (OMIM #182250) was initially described in two American females with abnormal dentition, distal limb osteoporosis, and marked calcification of the aortic arch and valve [17]. Since this original publication less than 20 individuals with SMS have been described in the literature [18–25]. The main characteristics of SMS include dental abnormalities such as a delay in primary tooth exfoliation and permanent tooth eruption as well as truncated tooth root formation, and root and alveolar bone resorption (Fig. 1A) [26]. Furthermore, SMS individuals develop severe calcifications of the ascending aorta and the aortic and mitral valves during adolescence (Fig. 1B) [13,26]. Common skeletal abnormalities are widened medullary cavities, distal-limb osteolysis and osteoporosis. Psoriasis, glaucoma, muscular weakness, scoliosis and an unusual face can be part of the SMS clinical picture [13,26]. The clinical features comprise a very variable interfamilial and intrafamilial phenotype. Individuals with a mild SMS phenotype may show only one symptom such as psoriasis. Individuals with a severe phenotype exhibit the main SMS features including cardiac calcifications as well as skeletal and dental abnormalities [13,26]. SMS is an autosomal-dominant inherited disorder. In a previous study, we identified a missense variant (c.2465G > A; p.Arg822Gln)

in the IFIH1 gene (OMIM *606951) as the cause of SMS [13]. IFIH1 consists of 16 exons and is localized on chromosome 2q24. It encodes for the 1025 amino acid melanoma differentiationassociated gene 5 (MDA5) protein, a cytoplasmic sensor for viral dsRNA. Structurally, MDA5 possesses two caspase activation recruitment domains (2CARD) at the N-terminus and a DExD/H motif helicase domain followed by the C-terminal domain (CTD, Fig. 2A). Because of the homologous domain composition MDA5 belongs to the RIG-I family receptors including RIG-I, MDA5 and LGP2 [27,28]. MDA5 was initially demonstrated to be a potential mediator of IFN induced growth inhibition factor in melanoma cells [29]. Andrejeva et al. showed that MDA5 is involved in the activation of the type I IFN signaling pathway in response to viral dsRNA [30]. Binding to dsRNA exclusively induces MDA5 assembling into a filament along the dsRNA axis in human and mouse [31–34]. Assembly of the MDA5 filament starts on the dsRNA interior and continues to the exterior in the absence of ATP. In contrary to this, ATP hydrolysis triggers independent disassembly of individual filaments from their ends. During dynamic equilibrium between assembly and ATP-driven end disassembly reactions, short filaments disassemble faster than longer ones, allowing continued elongation of longer filaments [31,32]. This positive role of ATP hydrolysis in MDA5 filament assembly reflects a continuous dynamic cycle of filament assembly and disassembly rather than a linear model of filament nucleation, elongation, and disassembly, resulting in a selective accumulation of MDA5 molecules on long dsRNA [31,32,35]. Studies on mutated MDA5 protein missing the 2CARD domain revealed that the two helicase domains and the CTD domain build a RNA recognition unit and form a ring-like structure around the dsRNA strand [33,36]. Thereby the CTD domain of MDA5 is differently orientated, facilitating the formation of MDA5 filaments [36,37]. MDA5 filament formation and binding to dsRNA allows the oligomerization of several 2CARD domains. The 2CARD oligomers interact with MAVS resulting in an active signaling complex [38]. Finally this complex activates different signal cascades such as NF-kB, IRF3, and AP-1 signaling, which induces the synthesis of type I IFN and IFN stimulated genes as well as pro-inflammatory cytokines [36,39] (Fig. 2A). The SMS-associated IFIH1 missense variant p.Arg822Gln is located in the highly conserved helicase domain [13]. Crystal structure analysis demonstrated that the mutation p.Arg822Gln is located next to the highly conserved amino acid motif composed of Gln818, Arg820, and Gly821 [13], that mediates conformational changes to create a high-affinity nucleic acid binding site [40]. The predicted conformational changes, caused by the p.Arg822Gln mutation, might lead to increased filament stability and permanent MDA5 activity (Fig. 2B). This hypothesis is supported by an

Fig. 1. Manifestations of Singleton-Merten syndrome (SMS). (A) Delayed eruption of primary teeth, early loss of rootless secondary teeth in a 19 year-old individual with SMS. (B) Calcified aortic valve from a 24 year-old individual with SMS. Subendocardial fibrosis and calcification (arrow) (HE staining). The aortic valve and the mitral valve had to be explanted and replaced in this patient due to massive valvular calcification.

Please cite this article in press as: I. Buers, et al., Novel interferonopathies associated with mutations in RIG-I like receptors, Cytokine Growth Factor Rev (2016), http://dx.doi.org/10.1016/j.cytogfr.2016.03.005

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Fig. 2. Simplified overview of RIG-I- and MDA5-mediated signaling pathway. (A) Diagram illustrating key features of RIG-I and MDA5. The sensors are composed of a central DExD/H box RNA helicase domain (helicase), which is essential to coordinate RNA binding and ATP hydrolysis activities. A C-terminal domain (CTD) is required for RNA terminus recognition and is involved in autoregulation. RIG-I and MDA5 contain tandem caspase activation and recruitment domain (CARD) regions at their N termini, which are essential for downstream signaling activity. Despite different ligand specificities for RNA or DNA, both RIG-I and MDA5 rely on the same signaling cascade to trigger the expression of type-1 IFNs and proinflammatory cytokines. Signaling is initiated by binding of RNA or DNA to the respective receptor (RIG-I or MDA5). These RNAs or DNAs trigger RIG-I or MDA5 filament formation and activate exposure of the 2CARD domain for interaction with the CARD of the signaling adaptor, MAVS. MAVS localizes in mitochondria and MAVS polymerization initiates intracellular signaling transduction leading to the activation of transcription factors of the IRF, NF-kB and AP-1 families. This ultimately leads to the production of type I IFN and inflammatory cytokines. (B) Abnormal activation of DNA/RNA sensing pathway leads to elevated IFN production. Mutation Arg822Gln in the MDA5 sensor (red flash) causes increased filament formation of MDA5 and leads to increased signaling.

altered type I IFN immune response identified by an enhanced IFN signature gene pattern in blood samples of SMS individuals. Additionally, cell culture experiments revealed that mutated MDA5 leads to an enhanced IFN response. Type I IFN mediates the activation of antigen presenting cells and enhances the

expression of major histocompatibility complex (MHC) molecules [41]. These findings support the idea that mutated MDA5 leads to a permanent IFN immune response due to conformational changes of MDA5.

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Recently Jang et al. described a phenotype similar to SMS called “atypical SMS” in 11 individuals of two families [42]. Atypical SMS (OMIM #616298) is characterized by glaucoma, aortic and valvular calcifications, and skeletal abnormalities. In contrast to classic SMS, dental abnormalities were absent in all cases of atypical SMS. Atypical SMS is caused by mono-allelic mutations (c.1118A > C; p.Glu373Ala or c.803G > T; p.Cys268Phe) in the DDX58 gene (OMIM *609631) [42]. DDX58 consists of 18 exons and is localized on chromosome 9p12. DDX58 encodes for the 925 amino acid RIG-I protein. RIG-I, as a member of the RIG-I family receptors and structurally similar to MDA5, consists of a helicase domain, a C-terminal repressor domain (RD) including the CTD domain, and the N-terminal 2CARD domain. The RD/CTD domain interacts with the CARD and the helicase domain. The CTD domain of RIG-I is the binding site for dsRNA, and overexpression of the RD domain disturbs RIG-I mediated signaling [27]. However, the 2CARD domain activates mitochondrial MAVS after dsRNA binding and thereby induces IFN signaling. RIG-I exists in two conditions: an inactive and an active form. In the absence of dsRNA the 2CARD domain of RIG-I is masked by the CTD domain. Binding of short dsRNAs containing 50 -triphosphate to the CTD domain activates the RIG-I protein, whereby the 2CARD domain is exposed through a conformational change [27,43]. This conformational change allows the oligomerization of several 2CARD domains and the formation of short RIG-I filaments. Similar to MDA5, the 2CARD oligomers of RIG-I filaments activate MAVS proteins in the mitochondrial membrane resulting in type I IFN immune response via the NF-kB, IRF3, and AP-1 signaling pathway [27]. The identified mutations in RIG-I causing atypical SMS are associated with enhanced NF-kB and PRDIII-I reporter gene activity and elevated IFNB1 and ISG15 expression patterns [42]. Additionally, Lässig et al. reported that mutations associated with atypical SMS lead to increased interaction of RIG-I with endogenous RNA and they speculated that RIG-I’s ATPase confers specificity to viral RNA by preventing signaling through the abundant background of selfRNA [44]. The data suggested that the identified mutations lead to constitutive activation of RIG-I associated with increased IFN activity. As described for MDA5, it is supposed that the identified mutations result in a conformational change of RIG-I protein, which leads to a gain-of-function [42]. 1.2. Systemic Lupus Erythematosus (SLE) SLE (OMIM #152700) is a systemic autoimmune disease associated with a multiplicity of symptoms including arthritis, joint pain, skin rash and tiredness, kidney disease and neuroinflammation [45]. In the last years, a variety of genetic factors have been identified to be associated with SLE [46,47]. High levels of type I IFN in many SLE individuals indicate that genetic factors might stimulate the type I IFN pathway [46,48]. Corresponding to this, different association studies provided evidence that common variants in genes of the IFN pathway such as IKBKE, NCF2, IKZF1, IRF8, and TYK2 are risk factors for SLE [46,49–51]. Additionally, most recently, a common coding-change polymorphism in IFIH1 (p.Ala946Thr, rs1990760) has been found to be associated to SLE [47,52–54]. This polymorphism is linked to increased levels of IFIH1 mRNA as well as elevated type I IFN and IFN induced gene expression suggesting a hyperactivity of this IFIH1 variant [51,53]. Although still considered a multifactorial disease, it is speculated that common gain-of-function variations in genes of the IFN signaling pathway contribute to the SLE phenotype [55]. Corroborating this hypothesis Van Eyck et al. identified a rare de novo gainof-function mutation (p.Arg779His) in the IFIH1 gene in a patient with severe early onset of SLE as a monogenic cause [15]. As expected the SLE individual showed elevated IFIH1 gene expression levels as well as high serum IFNa levels.

In 2014 a mouse model with a p.G821S mutation in Ifih1 was described [56]. This mutant mouse showed lupus like symptoms including skin rash and nephritis. Further findings included growth retardation and calcifications of the liver. Multiple organs of this mouse model show upregulation of IFN-b and RIG-I like receptor expression as well as elevated cytokine and chemokine levels. Crossbreeding with a MAVS deficient mouse model resulted in improvement of the symptoms, giving evidence that the identified Ifih1 mutation was responsible for the mouse phenotype. The p. G821S mutation was shown to be a gain-of-function mutation leading to a hyperactivity of the MDA5 protein due to conformational changes. Elevated sensitivity against dsRNA was excluded by the authors [56]. This mouse model supported the idea that gainof-function mutations in RIG-I like receptors result in hyperactivity of RIG-I like receptor proteins in a dsRNA independent manner. 1.3. Aicardi-Goutières-syndrome In 1984 Aicardi and Goutières described eight children with bilateral spasticity and dystonia, microcephaly, abnormal CSF lymphocytosis, calcifications of the basal ganglia and deep white matter hypodensities [57]. Since the first description more than 120 individuals with AGS have been reported. Some AGS patients show additional symptoms such as chilblains or glaucoma. AGS is a rare inborn disorder that is caused by autosomal recessive or autosomal dominant mutations in one of several genes. The main disease causing genes were identified in 2006 including TREX1 (three prime repair exonuclease 1), and genes encoding for ribonuclease H2 (RNASEH2) subunits RNASEH2A,RNASEH2B and RNASEH2C [58,59]. Then, mutations in the deoxynucleoside triphosphate triphosphohydrolase and ribonuclease SAM domain and HD domain 1 (SAMHD1), a regulator of innate immune response, were described to be associated with AGS [60,61]. Rice et al. identified mutations in the adenosine deaminases acting on RNA (ADAR) gene as an additional cause for AGS [62]. Mutations in these AGS causing genes lead to an elevated expression of IFN signature genes and therefore to a permanent IFN dependent immune response due to the accumulation of stimulatory RNA or DNA. Recently, eight dominant variants in the IFIH1 gene (p. Arg337Gly, p.Arg779Cys, p.Gly495Arg, p.Asp393Val, p.Arg720Gln, p.Arg779His, p.Ala452Thr, p.Leu372Phe) were independently identified in AGS individuals by two research groups [63,64]. All identified IFIH1 variants are mono-allelic missense mutations localized in the helicase domain of MDA5. Structural models of MDA5 reveal that all variants are located at the dsRNA or ATP binding sites within the helicase domain. Furthermore, all variants are associated with elevated type I IFN levels in vitro. Rice et al. demonstrated that cells transfected with mutated MDA5 are more sensitive against RNA analog polyinosinic:polycytidylic acid (poly I:C) than control cells resulting in a marked IFN signaling response [63]. They also showed that mutated MDA5 binds RNA more efficiently compared to wild type MDA5. Contrary to this, Oda et al. found that MDA5 might be constitutional activated independent from its ligand [64]. In conclusion both groups speculate that the AGS causing IFIH1 mutations stabilize MDA5 protein resulting in hyperactivity of the MDA5 protein. Recently, a family with three affected individuals with a heterogeneous phenotype was described by Bursztejn et al. [65]. The affected individuals show cutaneous symptoms similar to those of chilblain lupus. In this respect, ulcerating lesions of the ear were found in all individuals. Neurological manifestations such as bilateral calcifications of the globus pallidus were found in one family member. Additionally, this individual showed permanent tooth loss as well as hallux valgus. All affected individuals revealed elevated IFN patterns. Bursztein et al. identified a mono-allelic missense variant in the IFIH1 gene (p.Ala489Thr) in all affected

Please cite this article in press as: I. Buers, et al., Novel interferonopathies associated with mutations in RIG-I like receptors, Cytokine Growth Factor Rev (2016), http://dx.doi.org/10.1016/j.cytogfr.2016.03.005

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Table 1 Phenotypic spectrum associated with mutations in IFIH1.

SMSa SLE AGS Overlap AGS/ SMS Ref. [65] a

Early loss of Aortic Psoriasis Hallux permanent teeth calcification valgus

Wide medullary cavities phalanges

Glaucoma Calcification of basal ganglia

+ – – +

+ – – –

+ – + –

+ – – –

+ – – –

+ – – +

– – + +

Developmental delay/impairment

Chilblain lesion

Elevated IFN levels

– + + –

– – + +

+ + + +

Atypical SMS associated with mutations in DDX58 encoding for RIG-I shows a phenotype similar to SMS except for dental abnormalities.

individuals by whole-exome sequencing [65]. This variant also leads to an impaired ATP hydrolysis and increased stability of the MDA5 protein resulting in a significant enhancement of IFN signaling in the absence of exogenous RNA. Their study nicely corroborates the idea of a genotypic and phenotypic overlap of AGS with SMS. 2. Conclusion Recent genetic studies have identified mutations in RIG-I like receptors including MDA5 and RIG-I as the cause of rare autoimmune disorders. Gain-of-function mutations lead to constitutive interaction of these proteins with MAVS resulting in an active signaling complex, further activation of different signal cascades such as NF-kB, IRF3, and AP-1 signaling and induction of type I IFN synthesis. Based on their common pathogenetic pathway, it is reasonable that the phenotypes of the diseases associated with mutations in this pathway, including AGS, SLE and SMS show a considerable overlap (Table 1). Further studies aimed at the identification of contributing modifying factors and on tissue specific expression patterns of elements of the pathway will help to understand the phenotypic differences of the novel type I interferonopathies. Conflict of interest The authors declare that they do not have any conflicts of interest. Acknowledgements I.B. and F.R are supported by a grant from Innovative Medical Research, Münster University Hospital and by a grant from Interdisciplinary Clinical Research (IZKF), Münster University. F. R. and Y.N. are supported by a grant from the Deutsche Forschungsgemeinschaft DFG (RU 816-7-1). References [1] P. Lengyel, Biochemistry of interferons and their actions, Annu. Rev. Biochem. 51 (1982) 251–282. [2] S. Pestka, J.A. Langer, K.C. Zoon, C.E. Samuel, Interferons and their actions, Annu. Rev. Biochem. 56 (1987) 727–777. [3] G. Uzé, G. Schreiber, J. Piehler, S. Pellegrini, The receptor of the type I interferon family, Curr. Top. Microbiol. Immunol. 316 (2007) 71–95. [4] I. Gresser, L. Morel-Maroger, Y. Rivière, J.C. Guillon, M.G. Tovey, D. Woodrow, J. C. Sloper, J. Moss, Interferon-induced disease in mice and rats, Ann. N. Y. Acad. 350 (1980) 12–20. [5] P. Lebon, J. Badoual, G. Ponsot, F. Goutières, F. Hémeury-Cukier, J Aicardi, Intrathecal synthesis of interferon-a in infants with progressive familial encephalopathy, J. Neurol. Sci. 84 (1988) 201–208. [6] Y.J. Crow, Type I interferonopathies: a novel set of inborn errors of immunity, Ann. N. Y. Acad. Sci. 1238 (2011) 91–98. [7] T. Kawai, S. Akira, The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors, Nat. Immunol. 11 (2010) 373–384. [8] A. Varzari, K. Bruch, I.V. Deyneko, A. Chan, J.T. Epplen, S. Hoffjan, Analysis of polymorphisms in RIG-I-like receptor genes in German multiple sclerosis patients, J. Neuroimmunol. 277 (2014) 140–144.

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Please cite this article in press as: I. Buers, et al., Novel interferonopathies associated with mutations in RIG-I like receptors, Cytokine Growth Factor Rev (2016), http://dx.doi.org/10.1016/j.cytogfr.2016.03.005

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I. Buers et al. / Cytokine & Growth Factor Reviews xxx (2015) xxx–xxx associated with a heterozygous gain-of-function mutation in IFIH1: overlap between Aicardi-Goutières and Singleton-Merten syndromes, Br. J. Dermatol. 173 (2015) 1505–1513. Insa Buers did her PhD studies at the Leibniz-Institute for Arteriosclerosis Research. Since 2011 she is a member of Frank Rutsch’s group. Her main research interest is the characterization of molecular mechanisms of rare inborn metabolic disorders.

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Frank Rutsch is a consultant and Professor in Pediatrics at Münster University Children’s Hospital, Münster, Germany. He graduated from Münster University Medical School in 1992 and took part in the Pediatric residency program in Dresden and Dortmund, Germany. After spending a postdoctoral research fellowship at the Department of Rheumatology/Immunology, UCSD, San Diego, USA, he became the leader of an independent research group at Münster University Children’s Hospital in 2004. His main research interests are focused on the discovery of the underlying genetic defects and translational aspects in rare Pediatric metabolic and autoimmune disorders.

Yvonne Nitschke is a postdoctoral researcher in the group of Frank Rutsch. She is an expert on pathologic calcification processes.

Please cite this article in press as: I. Buers, et al., Novel interferonopathies associated with mutations in RIG-I like receptors, Cytokine Growth Factor Rev (2016), http://dx.doi.org/10.1016/j.cytogfr.2016.03.005