139 results on '"Rice GI"'
Search Results
2. Potential allelic burden of multiple variants in a complex case of undefined autoinflammatory syndrome
- Author
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Lamot, Lovro, Niemietz I, Tucker LB, Chung BK, Cabral AD, Houghton K, Petty RE, Morishita AK, Rice GI, Turvey SE, Gibson WT, and Brown KL
- Subjects
Autoinflammatory diseases - Abstract
Potential allelic burden of multiple variants in a complex case of undefined autoinflammatory syndrome
- Published
- 2019
3. Intracerebral large artery disease in Aicardi-Goutières syndrome implicates SAMHD1 in vascular homeostasis
- Author
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Ramesh, V, Bernardi, B, Stafa, A, Garone, Caterina, Franzoni, E, Abinun, M, Mitchell, P, Mitra, D, Friswell, M, Nelson, J, Shalev, Sa, Rice, Gi, Gornall, H, Szynkiewicz, M, Aymard, F, Ganesan, V, Prendiville, J, Livingston, Jh, Crow, Yj, Ramesh V, Bernardi B, Stafa A, Garone C, Franzoni E, Abinun M, Mitchell P, Mitra D, Friswell M, Nelson J, Shalev SA, Rice GI, Gornall H, Szynkiewicz M, Aymard F, Ganesan V, Prendiville J, Livingston JH, and Crow YJ
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Male ,DNA Mutational Analysis ,Infant ,Proteins ,Phosphoproteins ,SAM Domain and HD Domain-Containing Protein 1 ,Exodeoxyribonucleases ,Child, Preschool ,Homeostasis ,Humans ,Point Mutation ,Carotid Stenosis ,Female ,Cerebral Arterial Diseases ,Child ,Monomeric GTP-Binding Proteins - Abstract
AIM: To describe a spectrum of intracerebral large artery disease in Aicardi-Goutières syndrome (AGS) associated with mutations in the AGS5 gene SAMHD1. METHOD: We used clinical and radiological description and molecular analysis. RESULTS: Five individuals (three males, two females) were identified as having biallelic mutations in SAMHD1 and a cerebral arteriopathy in association with peripheral vessel involvement resulting in chilblains and ischaemic ulceration. The cerebral vasculopathy was primarily occlusive in three patients (with terminal carotid occlusion and basal collaterals reminiscent of moyamoya syndrome) and aneurysmal in two. Three of the five patients experienced intracerebral haemorrhage, which was fatal in two individuals. Post-mortem examination of one patient suggested that the arteriopathy was inflammatory in origin. INTERPRETATION: Mutations in SAMHD1 are associated with a cerebral vasculopathy which is likely to have an inflammatory aetiology. A similar disease has not been observed in patients with mutations in AGS1 to AGS4, suggesting a particular role for SAMHD1 in vascular homeostasis. Our report raises important questions about the management of patients with mutations in SAMHD1
- Published
- 2010
4. Gain of function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling
- Author
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Rice, Gi, Del Toro Duany, Y, Jenkinson, Em, Forte, Gm, Anderson, Bh, Ariaudo, G, Bader-Meunier, B, Baildm, Em, Battini, R, Beresford, Mw, Casarano, M, Chouchane, M, Cimaz, R, Collins, Ae, Cordeiro, Nj, Dale, Rc, Davidson, Je, Waelel, De, Desguerre, I, Faivre, L, Fazzi, E, Isidor, B, Lagae, L, Larchman, Ar, Lebon, P, Li, C, Livingston, Jh, Lourenço, Cm, Mancardi, Mm, Masurel-Paulet, A, Mcinnes, Ib, Menezes, Mp, Mignot, C, O'Sullivan, J, Orcesi, S, Picco, Pp, Riva, E, Robinson, Ra, Rodriguez, D, Salvatici, E, Scott, C, Szybowska, M, Tolmie, Jl, Vanderver, A, Vanhulle, C, Vieira, Jp, Webb, K, Whitney, Rn, Williams, Sg, Wolfe, La, Zuberi, Sm, Hur, S, and Crow, Yj
- Published
- 2014
5. Aicardi-Goutières syndrome presenting atypically as a sub-acute leukoencephalopathy
- Author
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Orcesi, S, Pessagno, A, Biancheri, R, LA PIANA, R, Mascaretti, M, Rossi, A, Rice, Gi, Crow, Yj, Fazzi, Elisa Maria, and Veneselli, E.
- Published
- 2008
6. Systemic lupus erythematosus due to C1q deficiency with progressive encephalopathy, intracranial calcification and acquired moyamoya cerebral vasculopathy
- Author
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Troedson, C, primary, Wong, M, additional, Dalby-Payne, J, additional, Wilson, M, additional, Dexter, M, additional, Rice, GI, additional, Crow, YJ, additional, and Dale, RC, additional
- Published
- 2013
- Full Text
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7. Aicardi-Goutières syndrome presenting with haematemesis in infancy
- Author
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Hall, D, primary, Rice, GI, additional, Akbar, N, additional, Meager, A, additional, Crow, YJ, additional, and Lim, MJ, additional
- Published
- 2009
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8. Intracerebral large artery disease in Aicardi-Goutières syndrome implicates SAMHD1 in vascular homeostasis.
- Author
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Ramesh V, Bernardi B, Stafa A, Garone C, Franzoni E, Abinun M, Mitchell P, Mitra D, Friswell M, Nelson J, Shalev SA, Rice GI, Gornall H, Szynkiewicz M, Aymard F, Ganesan V, Prendiville J, Livingston JH, and Crow YJ
- Abstract
Aim To describe a spectrum of intracerebral large artery disease in Aicardi-Goutières syndrome (AGS) associated with mutations in the AGS5 gene SAMHD1. Method We used clinical and radiological description and molecular analysis. Results Five individuals (three males, two females) were identified as having biallelic mutations in SAMHD1 and a cerebral arteriopathy in association with peripheral vessel involvement resulting in chilblains and ischaemic ulceration. The cerebral vasculopathy was primarily occlusive in three patients (with terminal carotid occlusion and basal collaterals reminiscent of moyamoya syndrome) and aneurysmal in two. Three of the five patients experienced intracerebral haemorrhage, which was fatal in two individuals. Post-mortem examination of one patient suggested that the arteriopathy was inflammatory in origin. Interpretation Mutations in SAMHD1 are associated with a cerebral vasculopathy which is likely to have an inflammatory aetiology. A similar disease has not been observed in patients with mutations in AGS1 to AGS4, suggesting a particular role for SAMHD1 in vascular homeostasis. Our report raises important questions about the management of patients with mutations in SAMHD1. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
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9. SAMHD1 restricts HIV-1 reverse transcription in quiescent CD4+ T-cells
- Author
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Descours Benjamin, Cribier Alexandra, Chable-Bessia Christine, Ayinde Diana, Rice Gillian, Crow Yanick, Yatim Ahmad, Schwartz Olivier, Laguette Nadine, and Benkirane Monsef
- Subjects
SAMHD1 ,Quiescent CD4+ T-cell ,HIV-1 ,Reverse transcription ,Restriction ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Abstract Background Quiescent CD4+ T lymphocytes are highly refractory to HIV-1 infection due to a block at reverse transcription. Results Examination of SAMHD1 expression in peripheral blood lymphocytes shows that SAMHD1 is expressed in both CD4+ and CD8+ T cells at levels comparable to those found in myeloid cells. Treatment of CD4+ T cells with Virus-Like Particles (VLP) containing Vpx results in the loss of SAMHD1 expression that correlates with an increased permissiveness to HIV-1 infection and accumulation of reverse transcribed viral DNA without promoting transcription from the viral LTR. Importantly, CD4+ T-cells from patients with Aicardi-Goutières Syndrome harboring mutation in the SAMHD1 gene display an increased susceptibility to HIV-1 infection that is not further enhanced by VLP-Vpx-treatment. Conclusion Here, we identified SAMHD1 as the restriction factor preventing efficient viral DNA synthesis in non-cycling resting CD4+ T-cells. These results highlight the crucial role of SAMHD1 in mediating restriction of HIV-1 infection in quiescent CD4+ T-cells and could impact our understanding of HIV-1 mediated CD4+ T-cell depletion and establishment of the viral reservoir, two of the HIV/AIDS hallmarks.
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- 2012
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10. Mutations in CTC1, encoding conserved telomere maintenance component 1, cause Coats plus
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Ram L. Kumar, Marjo S. van der Knaap, Sanjeev S. Bhaskar, Pierre-Yves Jeannet, John B.P. Stephenson, Gillian I. Rice, Joel Victor Fluss, James O'Sullivan, Raphael Schiffmann, Johannes A. Buckard, Andrea Whitney, Riyana Babul-Hirji, Catheline Vilain, Beverley Anderson, Yanick J. Crow, Emma M. Jenkinson, Gunnar Houge, Ewan Forrest, Vanessa Wermenbol, Peter Baxter, Sarah B. Daly, Marcin Szynkiewicz, Joanne Muter, Rosalind J. Jefferson, Wui K. Chong, Elisabeth Oppliger Leibundgut, Gabriela M. Baerlocher, Stefan Meyer, Jonathan E. Dickerson, Ramesh Mehta, Emma Wakeling, Sarah Risen, José Pedro Vieira, Sakkubai Naidu, Andrea Berger, Calvin Soh, John H. Livingston, David Chitayat, Staffan Lundberg, Simon C. Lovell, Luís Catela Nunes, Helen Stewart, Graeme C.M. Black, John Tolmie, Janice E Brunstom-Hernandez, Jill E. Urquhart, Josephine Mayer, Ghada M H Abdel-Salem, Paul R. Kasher, Charles Marques Lourenço, Simon Hammans, Emilio Franzoni, Caterina Garone, Katrin Õunap, Duccio Maria Cordelli, Prab Prabhakar, Ken K. Nischal, Luisa Bonafé, Michel Philippart, Sébastien Jacquemont, Patrick Ferreira, Imelda Hughes, Jon Stone, Georg Kutschke, Fluss, Joel Victor, Jeannet, Pierre-Yves, Pediatric surgery, NCA - Childhood White Matter Diseases, Anderson BH, Kasher PR, Mayer J, Szynkiewicz M, Jenkinson EM, Bhaskar SS, Urquhart JE, Daly SB, Dickerson JE, O'Sullivan J, Leibundgut EO, Muter J, Abdel-Salem GM, Babul-Hirji R, Baxter P, Berger A, Bonafé L, Brunstom-Hernandez JE, Buckard JA, Chitayat D, Chong WK, Cordelli DM, Ferreira P, Fluss J, Forrest EH, Franzoni E, Garone C, Hammans SR, Houge G, Hughes I, Jacquemont S, Jeannet PY, Jefferson RJ, Kumar R, Kutschke G, Lundberg S, Lourenço CM, Mehta R, Naidu S, Nischal KK, Nunes L, Ounap K, Philippart M, Prabhakar P, Risen SR, Schiffmann R, Soh C, Stephenson JB, Stewart H, Stone J, Tolmie JL, van der Knaap MS, Vieira JP, Vilain CN, Wakeling EL, Wermenbol V, Whitney A, Lovell SC, Meyer S, Livingston JH, Baerlocher GM, Black GC, Rice GI, Crow YJ, Other departments, and Neuroscience Campus Amsterdam - Childhood White Matter Diseases
- Subjects
DNA polymerase ,Molecular Sequence Data ,Telomere-Binding Proteins ,Histones/metabolism ,HDE GEN ,HDE NEU PED ,CST complex ,CEREBRORETINAL MICROANGIOPATHY, FAMILIAL SYNDROME, CALCIFICATIONS, CYSTS, PROTEIN, DNA, LEUKOENCEPHALOPATHY, EVOLUTION, DEFECTS ,Histones ,chemistry.chemical_compound ,Abnormalities, Multiple/genetics ,Genetics ,medicine ,Abnormalities, Multiple ,Genetic Predisposition to Disease ,Telomere-binding protein ,Telomere/pathology ,ddc:618 ,biology ,Base Sequence ,Genetic Predisposition to Disease/genetics ,DNA replication ,Sequence Analysis, DNA ,Telomere ,medicine.disease ,Flow Cytometry ,Cell biology ,Retinal Telangiectasis/genetics/pathology ,chemistry ,Sequence Analysis, DNA/methods ,biology.protein ,Retinal Telangiectasis ,Primase ,Telomere-Binding Proteins/genetics ,DNA ,Dyskeratosis congenita - Abstract
Coats plus is a highly pleiotropic disorder particularly affecting the eye, brain, bone and gastrointestinal tract. Here, we show that Coats plus results from mutations in CTC1, encoding conserved telomere maintenance component 1, a member of the mammalian homolog of the yeast heterotrimeric CST telomeric capping complex. Consistent with the observation of shortened telomeres in an Arabidopsis CTC1 mutant and the phenotypic overlap of Coats plus with the telomeric maintenance disorders comprising dyskeratosis congenita, we observed shortened telomeres in three individuals with Coats plus and an increase in spontaneous γ 3H2AX-positive cells in cell lines derived from two affected individuals. CTC1 is also a subunit of the I ±-accessory factor (AAF) complex, stimulating the activity of DNA polymerase-α, the only enzyme known to initiate DNA replication in eukaryotic cells. Thus, CTC1 may have a function in DNA metabolism that is necessary for but not specific to telomeric integrity. © 2012 Nature America, Inc. All rights reserved.
- Published
- 2012
11. Hereditary C1q Deficiency is Associated with Type 1 Interferon-Pathway Activation and a High Risk of Central Nervous System Inflammation.
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Triaille C, Rao NM, Rice GI, Seabra L, Sutherland FJH, Bondet V, Duffy D, Gennery AR, Fournier B, Bader-Meunier B, Troedson C, Cleary G, Buso H, Dalby-Payne J, Ranade P, Jansen K, De Somer L, Frémond ML, Chavan PP, Wong M, Dale RC, Wouters C, Quartier P, Khubchandani R, and Crow YJ
- Subjects
- Humans, Female, Male, Adult, Child, Adolescent, Young Adult, Signal Transduction, Middle Aged, Inflammation genetics, Interferon-alpha, Child, Preschool, Retrospective Studies, Complement C1q genetics, Complement C1q metabolism, Interferon Type I metabolism
- Abstract
Hereditary C1q deficiency (C1QDef) is a rare monogenic disorder leading to defective complement pathway activation and systemic lupus erythematosus (SLE)-like manifestations. The link between impairment of the complement cascade and autoimmunity remains incompletely understood. Here, we assessed type 1 interferon pathway activation in patients with C1QDef. Twelve patients with genetically confirmed C1QDef were recruited through an international collaboration. Clinical, biological and radiological data were collected retrospectively. The expression of a standardized panel of interferon stimulated genes (ISGs) in peripheral blood was measured, and the level of interferon alpha (IFNα) protein in cerebrospinal fluid (CSF) determined using SIMOA technology. Central nervous system (encompassing basal ganglia calcification, encephalitis, vasculitis, chronic pachymeningitis), mucocutaneous and renal involvement were present, respectively, in 10, 11 and 2 of 12 patients, and severe infections recorded in 2/12 patients. Elevated ISG expression was observed in all patients tested (n = 10/10), and serum and CSF IFNα elevated in 2/2 patients. Three patients were treated with Janus-kinase inhibitors (JAKi), with variable outcome; one displaying an apparently favourable response in respect of cutaneous and neurological features, and two others experiencing persistent disease despite JAKi therapy. To our knowledge, we report the largest original series of genetically confirmed C1QDef yet described. Additionally, we present a review of all previously described genetically confirmed cases of C1QDef. Overall, individuals with C1QDef demonstrate many characteristics of recognized monogenic interferonopathies: particularly, cutaneous involvement (malar rash, acral vasculitic/papular rash, chilblains), SLE-like disease, basal ganglia calcification, increased expression of ISGs in peripheral blood, and elevated levels of CSF IFNα., (© 2024. The Author(s).)
- Published
- 2024
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12. Gain-of-function human UNC93B1 variants cause systemic lupus erythematosus and chilblain lupus.
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David C, Arango-Franco CA, Badonyi M, Fouchet J, Rice GI, Didry-Barca B, Maisonneuve L, Seabra L, Kechiche R, Masson C, Cobat A, Abel L, Talouarn E, Béziat V, Deswarte C, Livingstone K, Paul C, Malik G, Ross A, Adam J, Walsh J, Kumar S, Bonnet D, Bodemer C, Bader-Meunier B, Marsh JA, Casanova JL, Crow YJ, Manoury B, Frémond ML, Bohlen J, and Lepelley A
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- Female, Humans, Male, Gain of Function Mutation, HEK293 Cells, Lupus Erythematosus, Cutaneous genetics, Lupus Erythematosus, Cutaneous pathology, Membrane Transport Proteins genetics, Membrane Transport Proteins metabolism, Mutation, Missense, Pedigree, Toll-Like Receptor 8 genetics, Toll-Like Receptor 8 metabolism, Child, Preschool, Child, Young Adult, Adult, Chilblains genetics, Lupus Erythematosus, Systemic genetics, Toll-Like Receptor 7 genetics, Toll-Like Receptor 7 metabolism
- Abstract
UNC93B1 is a transmembrane domain protein mediating the signaling of endosomal Toll-like receptors (TLRs). We report five families harboring rare missense substitutions (I317M, G325C, L330R, R466S, and R525P) in UNC93B1 causing systemic lupus erythematosus (SLE) or chilblain lupus (CBL) as either autosomal dominant or autosomal recessive traits. As for a D34A mutation causing murine lupus, we recorded a gain of TLR7 and, to a lesser extent, TLR8 activity with the I317M (in vitro) and G325C (in vitro and ex vivo) variants in the context of SLE. Contrastingly, in three families segregating CBL, the L330R, R466S, and R525P variants were isomorphic with respect to TLR7 activity in vitro and, for R525P, ex vivo. Rather, these variants demonstrated a gain of TLR8 activity. We observed enhanced interaction of the G325C, L330R, and R466S variants with TLR8, but not the R525P substitution, indicating different disease mechanisms. Overall, these observations suggest that UNC93B1 mutations cause monogenic SLE or CBL due to differentially enhanced TLR7 and TLR8 signaling., (© 2024 David et al.)
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- 2024
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13. A de novo TLR7 gain-of-function mutation causing severe monogenic lupus in an infant.
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Stremenova Spegarova J, Sinnappurajar P, Al Julandani D, Navickas R, Griffin H, Ahuja M, Grainger A, Livingstone K, Rice GI, Sutherland F, Hayes C, Parke S, Pang L, Roderick MR, Slatter M, Crow Y, Ramanan AV, and Hambleton S
- Subjects
- Humans, Infant, Female, Male, Lupus Erythematosus, Systemic genetics, Lupus Erythematosus, Systemic pathology, Toll-Like Receptor 7 genetics, Gain of Function Mutation
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- 2024
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14. Type I interferon regulates interleukin-1beta and IL-18 production and secretion in human macrophages.
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Díaz-Pino R, Rice GI, San Felipe D, Pepanashvili T, Kasher PR, Briggs TA, and López-Castejón G
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- Humans, Inflammasomes metabolism, Interleukin-1beta metabolism, Interleukin-18 metabolism, Macrophages metabolism, Cytokines metabolism, Inflammation metabolism, Caspase 1 metabolism, NLR Family, Pyrin Domain-Containing 3 Protein genetics, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, Interferon Type I metabolism
- Abstract
Inflammasomes are immune complexes whose activation leads to the release of pro-inflammatory cytokines IL-18 and IL-1β. Type I IFNs play a role in fighting infection and stimulate the expression of IFN-stimulated genes (ISGs) involved in inflammation. Despite the importance of these cytokines in inflammation, the regulation of inflammasomes by type I IFNs remains poorly understood. Here, we analysed RNA-sequencing data from patients with monogenic interferonopathies and found an up-regulation of several inflammasome-related genes. To investigate the effect of type I IFN on the inflammasome, we treated human monocyte-derived macrophages with IFN-α and observed an increase in CASP1 and GSDMD mRNA levels over time, whereas IL1B and NLRP3 were not directly correlated to IFN-α exposure time. IFN-α treatment reduced the release of mature IL-1β and IL-18, but not caspase-1, in response to ATP-mediated NLRP3 inflammasome activation, suggesting regulation occurs at cytokine expression levels and not the inflammasome itself. However, more studies are required to investigate how regulation by IFN-α occurs and impacts NLRP3 and other inflammasomes at both transcriptional and post-translational levels., (© 2024 Díaz-Pino et al.)
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- 2024
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15. Interface Gain-of-Function Mutations in TLR7 Cause Systemic and Neuro-inflammatory Disease.
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David C, Badonyi M, Kechiche R, Insalaco A, Zecca M, De Benedetti F, Orcesi S, Chiapparini L, Comoli P, Federici S, Gattorno M, Ginevrino M, Giorgio E, Matteo V, Moran-Alvarez P, Politano D, Prencipe G, Sirchia F, Volpi S, Masson C, Rice GI, Frémond ML, Lepelley A, Marsh JA, and Crow YJ
- Subjects
- Female, Male, Humans, Toll-Like Receptor 7, Mutation, Dimerization, RNA, Gain of Function Mutation, Lupus Erythematosus, Systemic
- Abstract
TLR7 recognizes pathogen-derived single-stranded RNA (ssRNA), a function integral to the innate immune response to viral infection. Notably, TLR7 can also recognize self-derived ssRNA, with gain-of-function mutations in human TLR7 recently identified to cause both early-onset systemic lupus erythematosus (SLE) and neuromyelitis optica. Here, we describe two novel mutations in TLR7, F507S and L528I. While the L528I substitution arose de novo, the F507S mutation was present in three individuals from the same family, including a severely affected male, notably given that the TLR7 gene is situated on the X chromosome and that all other cases so far described have been female. The observation of mutations at residues 507 and 528 of TLR7 indicates the importance of the TLR7 dimerization interface in maintaining immune homeostasis, where we predict that altered homo-dimerization enhances TLR7 signaling. Finally, while mutations in TLR7 can result in SLE-like disease, our data suggest a broader phenotypic spectrum associated with TLR7 gain-of-function, including significant neurological involvement., (© 2024. The Author(s).)
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- 2024
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16. JAK Inhibition in Aicardi-Goutières Syndrome: a Monocentric Multidisciplinary Real-World Approach Study.
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Frémond ML, Hully M, Fournier B, Barrois R, Lévy R, Aubart M, Castelle M, Chabalier D, Gins C, Sarda E, Al Adba B, Couderc S, D' Almeida C, Berat CM, Durrleman C, Espil C, Lambert L, Méni C, Périvier M, Pillet P, Polivka L, Schiff M, Todosi C, Uettwiller F, Lepelley A, Rice GI, Seabra L, Sanquer S, Hulin A, Pressiat C, Goldwirt L, Bondet V, Duffy D, Moshous D, Bader-Meunier B, Bodemer C, Robin-Renaldo F, Boddaert N, Blanche S, Desguerre I, Crow YJ, and Neven B
- Subjects
- Humans, Signal Transduction, Genetic Testing, Autoimmune Diseases of the Nervous System diagnosis, Autoimmune Diseases of the Nervous System drug therapy, Autoimmune Diseases of the Nervous System genetics, Nervous System Malformations diagnosis, Nervous System Malformations drug therapy, Nervous System Malformations genetics
- Abstract
The paradigm type I interferonopathy Aicardi-Goutières syndrome (AGS) is most typically characterized by severe neurological involvement. AGS is considered an immune-mediated disease, poorly responsive to conventional immunosuppression. Premised on a chronic enhancement of type I interferon signaling, JAK1/2 inhibition has been trialed in AGS, with clear improvements in cutaneous and systemic disease manifestations. Contrastingly, treatment efficacy at the level of the neurological system has been less conclusive. Here, we report our real-word approach study of JAK1/2 inhibition in 11 patients with AGS, providing extensive assessments of clinical and radiological status; interferon signaling, including in cerebrospinal fluid (CSF); and drug concentrations in blood and CSF. Over a median follow-up of 17 months, we observed a clear benefit of JAK1/2 inhibition on certain systemic features of AGS, and reproduced results reported using the AGS neurologic severity scale. In contrast, there was no change in other scales assessing neurological status; using the caregiver scale, only patient comfort, but no other domain of everyday-life care, was improved. Serious bacterial infections occurred in 4 out of the 11 patients. Overall, our data lead us to conclude that other approaches to treatment are urgently required for the neurologic features of AGS. We suggest that earlier diagnosis and adequate central nervous system penetration likely remain the major factors determining the efficacy of therapy in preventing irreversible brain damage, implying the importance of early and rapid genetic testing and the consideration of intrathecal drug delivery., (© 2023. The Author(s).)
- Published
- 2023
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17. Type I Interferonopathy due to a Homozygous Loss-of-Inhibitory Function Mutation in STAT2.
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Zhu G, Badonyi M, Franklin L, Seabra L, Rice GI, Anne-Boland-Auge, Deleuze JF, El-Chehadeh S, Anheim M, de Saint-Martin A, Pellegrini S, Marsh JA, Crow YJ, and El-Daher MT
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- Humans, Antibodies genetics, Gene Expression Regulation, Mutation genetics, Signal Transduction physiology, STAT1 Transcription Factor genetics, STAT1 Transcription Factor metabolism, STAT2 Transcription Factor genetics, STAT2 Transcription Factor chemistry, Transcriptional Activation, Ubiquitin Thiolesterase genetics, Ubiquitin Thiolesterase metabolism, Homozygote, Interferon Type I genetics
- Abstract
Purpose: STAT2 is both an effector and negative regulator of type I interferon (IFN-I) signalling. We describe the characterization of a novel homozygous missense STAT2 substitution in a patient with a type I interferonopathy., Methods: Whole-genome sequencing (WGS) was used to identify the genetic basis of disease in a patient with features of enhanced IFN-I signalling. After stable lentiviral reconstitution of STAT2-null human fibrosarcoma U6A cells with STAT2 wild type or p.(A219V), we performed quantitative polymerase chain reaction, western blotting, immunofluorescence, and co-immunoprecipitation to functionally characterize the p.(A219V) variant., Results: WGS identified a rare homozygous single nucleotide transition in STAT2 (c.656C > T), resulting in a p.(A219V) substitution, in a patient displaying developmental delay, intracranial calcification, and up-regulation of interferon-stimulated gene (ISG) expression in blood. In vitro studies revealed that the STAT2 p.(A219V) variant retained the ability to transduce an IFN-I stimulus. Notably, STAT2 p.(A219V) failed to support receptor desensitization, resulting in sustained STAT2 phosphorylation and ISG up-regulation. Mechanistically, STAT2 p.(A219V) showed defective binding to ubiquitin specific protease 18 (USP18), providing a possible explanation for the chronic IFN-I pathway activation seen in the patient., Conclusion: Our data indicate an impaired negative regulatory role of STAT2 p.(A219V) in IFN-I signalling and that mutations in STAT2 resulting in a type I interferonopathy state are not limited to the previously reported R148 residue. Indeed, structural modelling highlights at least 3 further residues critical to mediating a STAT2-USP18 interaction, in which mutations might be expected to result in defective negative feedback regulation of IFN-I signalling., (© 2023. The Author(s).)
- Published
- 2023
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18. Juvenile Neuropsychiatric Systemic Lupus Erythematosus: Identification of Novel Central Neuroinflammation Biomarkers.
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Labouret M, Costi S, Bondet V, Trebossen V, Le Roux E, Ntorkou A, Bartoli S, Auvin S, Bader-Meunier B, Baudouin V, Corseri O, Dingulu G, Ducrocq C, Dumaine C, Elmaleh M, Fabien N, Faye A, Hau I, Hentgen V, Kwon T, Meinzer U, Ouldali N, Parmentier C, Pouletty M, Renaldo F, Savioz I, Rozenberg F, Frémond ML, Lepelley A, Rice GI, Seabra L, Benoist JF, Duffy D, Crow YJ, Ellul P, and Melki I
- Subjects
- Humans, Child, Retrospective Studies, Neopterin, Neuroinflammatory Diseases, Biomarkers, Lupus Vasculitis, Central Nervous System, Lupus Erythematosus, Systemic diagnosis
- Abstract
Introduction: Juvenile systemic lupus erythematosus (j-SLE) is a rare chronic autoimmune disease affecting multiple organs. Ranging from minor features, such as headache or mild cognitive impairment, to serious and life-threatening presentations, j-neuropsychiatric SLE (j-NPSLE) is a therapeutic challenge. Thus, the diagnosis of NPSLE remains difficult, especially in pediatrics, with no specific biomarker of the disease yet validated., Objectives: To identify central nervous system (CNS) disease biomarkers of j-NPSLE., Methods: A 5-year retrospective tertiary reference monocentric j-SLE study. A combination of standardized diagnostic criteria and multidisciplinary pediatric clinical expertise was combined to attribute NP involvement in the context of j-SLE. Neopterin and interferon-alpha (IFN-α) protein levels in cerebrospinal fluid (CSF) were assessed, together with routine biological and radiological investigations., Results: Among 51 patients with j-SLE included, 39% presented with j-NPSLE. J-NPSLE was diagnosed at onset of j-SLE in 65% of patients. No specific routine biological or radiological marker of j-NPSLE was identified. However, CSF neopterin levels were significantly higher in active j-NPSLE with CNS involvement than in j-SLE alone (p = 0.0008). Neopterin and IFN-α protein levels in CSF were significantly higher at diagnosis of j-NPSLE with CNS involvement than after resolution of NP features (respectively p = 0.0015 and p = 0.0010) upon immunosuppressive treatment in all patients tested (n = 10). Both biomarkers correlated strongly with each other (R
s = 0.832, p < 0.0001, n = 23 paired samples)., Conclusion: CSF IFN-α and neopterin constitute promising biomarkers useful in the diagnosis and monitoring of activity in j-NPSLE., (© 2022. The Author(s).)- Published
- 2023
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19. Characterization of a mutant samhd1 zebrafish model implicates dysregulation of cholesterol biosynthesis in Aicardi-Goutières syndrome.
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Withers SE, Rowlands CF, Tapia VS, Hedley F, Mosneag IE, Crilly S, Rice GI, Badrock AP, Hayes A, Allan SM, Briggs TA, and Kasher PR
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- Animals, Mice, SAM Domain and HD Domain-Containing Protein 1 genetics, Zebrafish genetics, Zebrafish metabolism, Autoimmune Diseases of the Nervous System genetics, Autoimmune Diseases of the Nervous System metabolism, Interferon Type I genetics, Interferon Type I metabolism, Nervous System Malformations genetics, Nervous System Malformations metabolism
- Abstract
Aicardi-Goutières syndrome (AGS1-9) is a genetically determined encephalopathy that falls under the type I interferonopathy disease class, characterized by excessive type I interferon (IFN-I) activity, coupled with upregulation of IFN-stimulated genes (ISGs), which can be explained by the vital role these proteins play in self-non-self-discrimination. To date, few mouse models fully replicate the vast clinical phenotypes observed in AGS patients. Therefore, we investigated the use of zebrafish as an alternative species for generating a clinically relevant model of AGS. Using CRISPR-cas9 technology, we generated a stable mutant zebrafish line recapitulating AGS5, which arises from recessive mutations in SAMHD1 . The resulting homozygous mutant zebrafish larvae possess a number of neurological phenotypes, exemplified by variable, but increased expression of several ISGs in the head region, a significant increase in brain cell death, microcephaly and locomotion deficits. A link between IFN-I signaling and cholesterol biosynthesis has been highlighted by others, but not previously implicated in the type I interferonopathies. Through assessment of neurovascular integrity and qPCR analysis we identified a significant dysregulation of cholesterol biosynthesis in the zebrafish model. Furthermore, dysregulation of cholesterol biosynthesis gene expression was also observed through RNA sequencing analysis of AGS patient whole blood. From this novel finding, we hypothesize that cholesterol dysregulation may play a role in AGS disease pathophysiology. Further experimentation will lend critical insight into the molecular pathophysiology of AGS and the potential links involving aberrant type I IFN signaling and cholesterol dysregulation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Withers, Rowlands, Tapia, Hedley, Mosneag, Crilly, Rice, Badrock, Hayes, Allan, Briggs and Kasher.)
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- 2023
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20. DNASE1L3 deficiency, new phenotypes, and evidence for a transient type I IFN signaling.
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Tusseau M, Lovšin E, Samaille C, Pescarmona R, Mathieu AL, Maggio MC, Selmanović V, Debeljak M, Dachy A, Novljan G, Janin A, Januel L, Gibier JB, Chopin E, Rouvet I, Goncalves D, Fabien N, Rice GI, Lesca G, Labalme A, Romagnani P, Walzer T, Viel S, Perret M, Crow YJ, Avčin T, Cimaz R, and Belot A
- Subjects
- Antibodies, Antineutrophil Cytoplasmic genetics, Chromatin, DNA, Humans, Interferons, Phenotype, Endodeoxyribonucleases genetics, Endodeoxyribonucleases metabolism, Inflammatory Bowel Diseases, Interferon Type I genetics, Lupus Erythematosus, Systemic genetics, Lupus Nephritis diagnosis, Lupus Nephritis genetics, Vasculitis diagnosis
- Abstract
Background: Deoxyribonuclease 1 like 3 (DNASE1L3) is a secreted enzyme that has been shown to digest the extracellular chromatin derived from apoptotic bodies, and DNASE1L3 pathogenic variants have been associated with a lupus phenotype. It is unclear whether interferon signaling is sustained in DNASE1L3 deficiency in humans., Objectives: To explore interferon signaling in DNASE1L3 deficient patients. To depict the characteristic features of DNASE1L3 deficiencies in human., Methods: We identified, characterized, and analyzed five new patients carrying biallelic DNASE1L3 variations. Whole or targeted exome and/or Sanger sequencing was performed to detect pathogenic variations in five juvenile systemic erythematosus lupus (jSLE) patients. We measured interferon-stimulated gene (ISG) expression in all patients. We performed a systematic review of all published cases available from its first description in 2011 to March 24
th 2022., Results: We identified five new patients carrying biallelic DNASE1L3 pathogenic variations, including three previously unreported mutations. Contrary to canonical type I interferonopathies, we noticed a transient increase of ISGs in blood, which returned to normal with disease remission. Disease in one patient was characterized by lupus nephritis and skin lesions, while four others exhibited hypocomplementemic urticarial vasculitis syndrome. The fourth patient presented also with early-onset inflammatory bowel disease. Reviewing previous reports, we identified 35 additional patients with DNASE1L3 deficiency which was associated with a significant risk of lupus nephritis and a poor outcome together with the presence of anti-neutrophil cytoplasmic antibodies (ANCA). Lung lesions were reported in 6/35 patients., Conclusions: DNASE1L3 deficiencies are associated with a broad phenotype including frequently lupus nephritis and hypocomplementemic urticarial vasculitis with positive ANCA and rarely, alveolar hemorrhages and inflammatory bowel disease. This report shows that interferon production is transient contrary to anomalies of intracellular DNA sensing and signaling observed in Aicardi-Goutières syndrome or STING-associated vasculitis in infancy (SAVI)., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)- Published
- 2022
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21. Mutations in RNU7-1 Weaken Secondary RNA Structure, Induce MCP-1 and CXCL10 in CSF, and Result in Aicardi-Goutières Syndrome with Severe End-Organ Involvement.
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Naesens L, Nemegeer J, Roelens F, Vallaeys L, Meuwissen M, Janssens K, Verloo P, Ogunjimi B, Hemelsoet D, Hoste L, Roels L, De Bruyne M, De Baere E, Van Dorpe J, Dendooven A, Sieben A, Rice GI, Kerre T, Beyaert R, Uggenti C, Crow YJ, Tavernier SJ, Maelfait J, and Haerynck F
- Subjects
- Chemokine CXCL10 genetics, Histones, Humans, Interferons, Mutation, RNA, RNA Precursors chemistry, RNA Precursors genetics, RNA Precursors metabolism, RNA-Binding Proteins genetics, Autoimmune Diseases of the Nervous System diagnosis, Autoimmune Diseases of the Nervous System genetics, Nervous System Malformations diagnosis, Nervous System Malformations genetics, RNA, Small Nuclear genetics
- Abstract
Background: Aicardi-Goutières syndrome (AGS) is a type I interferonopathy usually characterized by early-onset neurologic regression. Biallelic mutations in LSM11 and RNU7-1, components of the U7 small nuclear ribonucleoprotein (snRNP) complex, have been identified in a limited number of genetically unexplained AGS cases. Impairment of U7 snRNP function results in misprocessing of replication-dependent histone (RDH) pre-mRNA and disturbance of histone occupancy of nuclear DNA, ultimately driving cGAS-dependent type I interferon (IFN-I) release., Objective: We performed a clinical, genetic, and immunological workup of 3 unrelated patients with uncharacterized AGS., Methods: Whole exome sequencing (WES) and targeted Sanger sequencing of RNU7-1 were performed. Primary fibroblasts were used for mechanistic studies. IFN-I signature and STAT1/2 phosphorylation were assessed in peripheral blood. Cytokines were profiled on serum and cerebrospinal fluid (CSF). Histopathology was examined on brain and kidney tissue., Results: Sequencing revealed compound heterozygous RNU7-1 mutations, resulting in impaired RDH pre-mRNA processing. The 3' stem-loop mutations reduced stability of the secondary U7 snRNA structure. A discrete IFN-I signature in peripheral blood was paralleled by MCP-1 (CCL2) and CXCL10 upregulation in CSF. Histopathological analysis of the kidney showed thrombotic microangiopathy. We observed dysregulated STAT phosphorylation upon cytokine stimulation. Clinical overview of all reported patients with RNU7-1-related disease revealed high mortality and high incidence of organ involvement compared to other AGS genotypes., Conclusions: Targeted RNU7-1 sequencing is recommended in genetically unexplained AGS cases. CSF cytokine profiling represents an additional diagnostic tool to identify aberrant IFN-I signaling. Clinical follow-up of RNU7-1-mutated patients should include screening for severe end-organ involvement including liver disease and nephropathy., (© 2022. The Author(s).)
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- 2022
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22. Systemic inflammatory syndrome in children with FARSA deficiency.
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Charbit-Henrion F, Goguyer-Deschaumes R, Borensztajn K, Mirande M, Berthelet J, Rodrigues-Lima F, Khiat A, Frémond ML, Bader-Meunier B, Rodari MM, Seabra L, Rice GI, Legendre M, Drummond D, Berteloot L, Roux CJ, Boddaert N, Drabent P, Molina TJ, Lacaille F, Kossorotoff M, Cerf-Bensussan N, Parlato M, and Hadchouel A
- Subjects
- Consanguinity, Humans, Phenotype, Syndrome, Amino Acyl-tRNA Synthetases genetics, Charcot-Marie-Tooth Disease genetics, Lung Diseases, Interstitial genetics
- Abstract
Variants in aminoacyl-tRNA synthetases (ARSs) genes are associated to a broad spectrum of human inherited diseases. Patients with defective PheRS, encoded by FARSA and FARSB, display brain abnormalities, interstitial lung disease and facial dysmorphism. We investigated four children from two unrelated consanguineous families carrying two missense homozygous variants in FARSA with significantly reduced PheRS-mediated aminoacylation activity. In addition to the core ARS-phenotype, all patients showed an inflammatory profile associated with autoimmunity and interferon score, a clinical feature not ascribed to PheRS-deficient patients to date. JAK inhibition improved lung disease in one patient. Our findings expand the genetic and clinical spectrum of FARSA-related disease., (© 2022 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.)
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- 2022
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23. Enhanced cGAS-STING-dependent interferon signaling associated with mutations in ATAD3A.
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Lepelley A, Della Mina E, Van Nieuwenhove E, Waumans L, Fraitag S, Rice GI, Dhir A, Frémond ML, Rodero MP, Seabra L, Carter E, Bodemer C, Buhas D, Callewaert B, de Lonlay P, De Somer L, Dyment DA, Faes F, Grove L, Holden S, Hully M, Kurian MA, McMillan HJ, Suetens K, Tyynismaa H, Chhun S, Wai T, Wouters C, Bader-Meunier B, and Crow YJ
- Subjects
- ATPases Associated with Diverse Cellular Activities metabolism, Child, Child, Preschool, DNA, Mitochondrial genetics, DNA, Mitochondrial metabolism, Female, Genes, Dominant, Humans, Interferons genetics, Male, Mitochondrial Proteins metabolism, Nucleotidyltransferases genetics, Scleroderma, Systemic genetics, Scleroderma, Systemic pathology, Signal Transduction, THP-1 Cells, Young Adult, ATPases Associated with Diverse Cellular Activities genetics, Interferons metabolism, Membrane Proteins genetics, Membrane Proteins metabolism, Mitochondrial Proteins genetics, Mutation, Nucleotidyltransferases metabolism
- Abstract
Mitochondrial DNA (mtDNA) has been suggested to drive immune system activation, but the induction of interferon signaling by mtDNA has not been demonstrated in a Mendelian mitochondrial disease. We initially ascertained two patients, one with a purely neurological phenotype and one with features suggestive of systemic sclerosis in a syndromic context, and found them both to demonstrate enhanced interferon-stimulated gene (ISG) expression in blood. We determined each to harbor a previously described de novo dominant-negative heterozygous mutation in ATAD3A, encoding ATPase family AAA domain-containing protein 3A (ATAD3A). We identified five further patients with mutations in ATAD3A and recorded up-regulated ISG expression and interferon α protein in four of them. Knockdown of ATAD3A in THP-1 cells resulted in increased interferon signaling, mediated by cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING). Enhanced interferon signaling was abrogated in THP-1 cells and patient fibroblasts depleted of mtDNA. Thus, mutations in the mitochondrial membrane protein ATAD3A define a novel type I interferonopathy., Competing Interests: Disclosures: E. Van Nieuwenhove reported grants from FWO/Research Foundation Flanders (SB grant 1S22718N) during the conduct of the study. No other disclosures were reported., (© 2021 Lepelley et al.)
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- 2021
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24. Differential levels of IFNα subtypes in autoimmunity and viral infection.
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Bondet V, Rodero MP, Posseme C, Bost P, Decalf J, Haljasmägi L, Bekaddour N, Rice GI, Upasani V, Herbeuval JP, Reynolds JA, Briggs TA, Bruce IN, Mauri C, Isenberg D, Menon M, Hunt D, Schwikowski B, Mariette X, Pol S, Rozenberg F, Cantaert T, Eric Gottenberg J, Kisand K, and Duffy D
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- Adolescent, Adult, Aged, Child, Child, Preschool, Female, Humans, Infant, Male, Middle Aged, Young Adult, Antiviral Agents immunology, Autoimmunity immunology, Interferon-alpha immunology, Virus Diseases immunology
- Abstract
Type I interferons are essential for host response to viral infections, while dysregulation of their response can result in autoinflammation or autoimmunity. Among IFNα (alpha) responses, 13 subtypes exist that signal through the same receptor, but have been reported to have different effector functions. However, the lack of available tools for discriminating these closely related subtypes, in particular at the protein level, has restricted the study of their differential roles in disease. We developed a digital ELISA with specificity and high sensitivity for the IFNα2 subtype. Application of this assay, in parallel with our previously described pan-IFNα assay, allowed us to study different IFNα protein responses following cellular stimulation and in diverse patient cohorts. We observed different ratios of IFNα protein responses between viral infection and autoimmune patients. This analysis also revealed a small percentage of autoimmune patients with high IFNα2 protein measurements but low pan-IFNα measurements. Correlation with an ISG score and functional activity showed that in this small sub group of patients, IFNα2 protein measurements did not reflect its biological activity. This unusual phenotype was partly explained by the presence of anti-IFNα auto-antibodies in a subset of autoimmune patients. This study reports ultrasensitive assays for the study of IFNα proteins in patient samples and highlights the insights that can be obtained from the use of multiple phenotypic readouts in translational and clinical studies., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
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- 2021
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25. From Diagnosis to Prognosis: Revisiting the Meaning of Muscle ISG15 Overexpression in Juvenile Inflammatory Myopathies.
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Hou C, Durrleman C, Periou B, Barnerias C, Bodemer C, Desguerre I, Quartier P, Melki I, Rice GI, Rodero MP, Charuel JL, Relaix F, Bader-Meunier B, Authier F, and Gitiaux C
- Subjects
- Adolescent, Autoantibodies immunology, Biomarkers, Case-Control Studies, Child, Child, Preschool, DEAD Box Protein 58 metabolism, Dermatomyositis diagnosis, Dermatomyositis physiopathology, Female, Humans, Immunohistochemistry, Interferon-Induced Helicase, IFIH1 metabolism, Male, Muscle, Skeletal metabolism, Muscular Dystrophy, Duchenne metabolism, Myopathies, Structural, Congenital metabolism, Myositis diagnosis, Myositis metabolism, Myositis physiopathology, Prognosis, Real-Time Polymerase Chain Reaction, Receptors, Immunologic metabolism, Ubiquitin Thiolesterase metabolism, Cytokines metabolism, Dermatomyositis metabolism, Ubiquitins metabolism
- Abstract
Objective: Juvenile idiopathic inflammatory/immune myopathies (IIMs) constitute a highly heterogeneous group of disorders with diagnostic difficulties and prognostic uncertainties. Circulating myositis-specific autoantibodies (MSAs) have been recognized as reliable tools for patient substratification. Considering the key role of type I interferon (IFN) up-regulation in juvenile IIM, we undertook the present study to investigate whether IFN-induced 15-kd protein (ISG-15) could be a reliable biomarker for stratification and diagnosis and to better elucidate its role in juvenile IIM pathophysiology., Methods: The study included 56 patients: 24 with juvenile dermatomyositis (DM), 12 with juvenile overlap myositis (OM), 10 with Duchenne muscular dystrophy, and 10 with congenital myopathies. Muscle biopsy samples were assessed by immunohistochemistry, immunoblotting, and real-time quantitative polymerase chain reaction. Negative regulators of type I IFN (ISG15 and USP18) and positive regulators of type I IFN (DDX58 and IFIH1) were analyzed., Results: ISG15 expression discriminated patients with juvenile IIM from those with nonimmune myopathies and, among patients with juvenile IIM, discriminated those with DM from those with OM. Among patients with juvenile DM, up-regulation of the type I IFN positive regulators DDX58 and IFIH1 was similar regardless of MSA status. In contrast, the highest levels of the type I IFN negative regulator ISG15 were observed in patients who were positive for melanoma differentiation-associated gene 5 (MDA-5). Finally, ISG15 levels were inversely correlated with the severity of muscle histologic abnormalities and positively correlated with motor performance as evaluated by the Childhood Myositis Assessment Scale and by manual muscle strength testing., Conclusion: Muscle ISG15 expression is strongly associated with juvenile DM, with patients exhibiting a different ISG-15 muscle signature according to their MSA class. Patients with juvenile DM who are positive for MDA-5 have higher expression of ISG15 in both gene form and protein form compared to the other subgroups. Moreover, our data show that negative regulation of type I IFN correlates with milder muscle involvement., (© 2020, American College of Rheumatology.)
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- 2021
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26. Differential Expression of Interferon-Alpha Protein Provides Clues to Tissue Specificity Across Type I Interferonopathies.
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Lodi L, Melki I, Bondet V, Seabra L, Rice GI, Carter E, Lepelley A, Martin-Niclós MJ, Al Adba B, Bader-Meunier B, Barth M, Blauwblomme T, Bodemer C, Boespflug-Tanguy O, Dale RC, Desguerre I, Ducrocq C, Dulieu F, Dumaine C, Ellul P, Hadchouel A, Hentgen V, Hié M, Hully M, Jeziorski E, Lévy R, Mochel F, Orcesi S, Passemard S, Pouletty M, Quartier P, Renaldo F, Seidl R, Shetty J, Neven B, Blanche S, Duffy D, Crow YJ, and Frémond ML
- Subjects
- Adolescent, Adult, Case-Control Studies, Child, Child, Preschool, Female, Humans, Infant, Interferon Type I cerebrospinal fluid, Interferon Type I metabolism, Interferon-alpha cerebrospinal fluid, Interferon-alpha metabolism, Male, Mutation, Phenotype, Retrospective Studies, Young Adult, Disease Susceptibility, Gene Expression Regulation, Interferon Type I genetics, Interferon-alpha genetics, Organ Specificity genetics
- Abstract
Whilst upregulation of type I interferon (IFN) signaling is common across the type I interferonopathies (T1Is), central nervous system (CNS) involvement varies between these disorders, the basis of which remains unclear. We collected cerebrospinal fluid (CSF) and serum from patients with Aicardi-Goutières syndrome (AGS), STING-associated vasculopathy with onset in infancy (SAVI), presumed monogenic T1Is (pT1I), childhood systemic lupus erythematosus with neuropsychiatric features (nSLE), non-IFN-related autoinflammation (AI) and non-inflammatory hydrocephalus (as controls). We measured IFN-alpha protein using digital ELISA. Eighty-two and 63 measurements were recorded respectively in CSF and serum of 42 patients and 6 controls. In an intergroup comparison (taking one sample per individual), median CSF IFN-alpha levels were elevated in AGS, SAVI, pT1I, and nSLE compared to AI and controls, with levels highest in AGS compared to all other groups. In AGS, CSF IFN-alpha concentrations were higher than in paired serum samples. In contrast, serum IFN was consistently higher compared to CSF levels in SAVI, pT1I, and nSLE. Whilst IFN-alpha is present in the CSF and serum of all IFN-related diseases studied here, our data suggest the primary sites of IFN production in the monogenic T1I AGS and SAVI are, respectively, the CNS and the periphery. These results inform the diagnosis of, and future therapeutic approaches to, monogenic and multifactorial T1Is.
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- 2021
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27. LACC1 deficiency links juvenile arthritis with autophagy and metabolism in macrophages.
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Omarjee O, Mathieu AL, Quiniou G, Moreews M, Ainouze M, Frachette C, Melki I, Dumaine C, Gerfaud-Valentin M, Duquesne A, Kallinich T, Tahir Turanli E, Malcus C, Viel S, Pescarmona R, Georgin-Lavialle S, Jamilloux Y, Larbre JP, Sarrabay G, Magnotti F, Rice GI, Bleicher F, Reboulet J, Merabet S, Henry T, Crow YJ, Faure M, Walzer T, and Belot A
- Subjects
- Adenylate Kinase metabolism, Adolescent, Amino Acid Sequence, Apoptosis drug effects, Arthritis, Juvenile genetics, Autophagy-Related Proteins metabolism, Bacteria metabolism, Cell Differentiation drug effects, Child, Exome genetics, Female, Homozygote, Humans, Inflammasomes metabolism, Inflammation complications, Inflammation pathology, Interferons metabolism, Intracellular Signaling Peptides and Proteins chemistry, Intracellular Signaling Peptides and Proteins genetics, Lipid Droplets drug effects, Lipid Droplets metabolism, Loss of Function Mutation genetics, Lysosomes drug effects, Lysosomes metabolism, Macrophage Colony-Stimulating Factor pharmacology, Macrophages drug effects, Male, Mitochondria drug effects, Mitochondria metabolism, Monocytes drug effects, Monocytes pathology, NF-kappa B metabolism, Pedigree, Proteomics, Receptors for Activated C Kinase metabolism, Signal Transduction, TOR Serine-Threonine Kinases metabolism, Young Adult, Arthritis, Juvenile metabolism, Arthritis, Juvenile pathology, Autophagy drug effects, Autophagy genetics, Intracellular Signaling Peptides and Proteins deficiency, Macrophages metabolism
- Abstract
Juvenile idiopathic arthritis is the most common chronic rheumatic disease in children, and its etiology remains poorly understood. Here, we explored four families with early-onset arthritis carrying homozygous loss-of-expression mutations in LACC1. To understand the link between LACC1 and inflammation, we performed a functional study of LACC1 in human immune cells. We showed that LACC1 was primarily expressed in macrophages upon mTOR signaling. We found that LACC1 deficiency had no obvious impact on inflammasome activation, type I interferon response, or NF-κB regulation. Using bimolecular fluorescence complementation and biochemical assays, we showed that autophagy-inducing proteins, RACK1 and AMPK, interacted with LACC1. Autophagy blockade in macrophages was associated with LACC1 cleavage and degradation. Moreover, LACC1 deficiency reduced autophagy flux in primary macrophages. This was associated with a defect in the accumulation of lipid droplets and mitochondrial respiration, suggesting that LACC1-dependent autophagy fuels macrophage bioenergetics metabolism. Altogether, LACC1 deficiency defines a novel form of genetically inherited juvenile arthritis associated with impaired autophagy in macrophages., Competing Interests: Disclosures: S. Georgin-Lavialle reported personal fees from SOBI, non-financial support from Novartis, and personal fees from BMS outside the submitted work. F. Bleicher reported a patent to FR1655539 pending. J. Reboulet reported a patent to FR1655539 issued. S. Merabet reported a patent to FR1655539 pending. T. Henry reported personal fees from SOBI and grants from SOBI outside the submitted work. No other disclosures were reported., (© 2021 Omarjee et al.)
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- 2021
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28. Overview of STING-Associated Vasculopathy with Onset in Infancy (SAVI) Among 21 Patients.
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Frémond ML, Hadchouel A, Berteloot L, Melki I, Bresson V, Barnabei L, Jeremiah N, Belot A, Bondet V, Brocq O, Chan D, Dagher R, Dubus JC, Duffy D, Feuillet-Soummer S, Fusaro M, Gattorno M, Insalaco A, Jeziorski E, Kitabayashi N, Lopez-Corbeto M, Mazingue F, Morren MA, Rice GI, Rivière JG, Seabra L, Sirvente J, Soler-Palacin P, Stremler-Le Bel N, Thouvenin G, Thumerelle C, Van Aerde E, Volpi S, Willcocks S, Wouters C, Breton S, Molina T, Bader-Meunier B, Moshous D, Fischer A, Blanche S, Rieux-Laucat F, Crow YJ, and Neven B
- Subjects
- Adolescent, Adult, Child, Humans, Infant, Inflammation, Mutation, Lung Diseases, Interstitial, Membrane Proteins genetics, Vascular Diseases
- Abstract
Background: Gain-of-function mutations in STING1 underlie a type I interferonopathy termed SAVI (STING-associated vasculopathy with onset in infancy). This severe disease is variably characterized by early-onset systemic inflammation, skin vasculopathy, and interstitial lung disease (ILD)., Objective: To describe a cohort of patients with SAVI., Methods: Assessment of clinical, radiological and immunological data from 21 patients (17 families) was carried out., Results: Patients carried heterozygous substitutions in STING1 previously described in SAVI, mainly the p.V155M. Most were symptomatic from infancy, but late onset in adulthood occurred in 1 patient. Systemic inflammation, skin vasculopathy, and ILD were observed in 19, 18, and 21 patients, respectively. Extensive tissue loss occurred in 4 patients. Severity of ILD was highly variable with insidious progression up to end-stage respiratory failure reached at teenage in 6 patients. Lung imaging revealed early fibrotic lesions. Failure to thrive was almost constant, with severe growth failure seen in 4 patients. Seven patients presented polyarthritis, and the phenotype in 1 infant mimicked a combined immunodeficiency. Extended features reminiscent of other interferonopathies were also found, including intracranial calcification, glaucoma and glomerular nephropathy. Increased expression of interferon-stimulated genes and interferon α protein was constant. Autoantibodies were frequently found, in particular rheumatoid factor. Most patients presented with a T-cell defect, with low counts of memory CD8+ cells and impaired T-cell proliferation in response to antigens. Long-term follow-up described in 8 children confirmed the clinical benefit of ruxolitinib in SAVI where the treatment was started early in the disease course, underlying the need for early diagnosis. Tolerance was reasonably good., Conclusion: The largest worldwide cohort of SAVI patients yet described, illustrates the core features of the disease and extends the clinical and immunological phenotype to include overlap with other monogenic interferonopathies., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)
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- 2021
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29. Leukoencephalopathy with calcifications and cysts: Genetic and phenotypic spectrum.
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Crow YJ, Marshall H, Rice GI, Seabra L, Jenkinson EM, Baranano K, Battini R, Berger A, Blair E, Blauwblomme T, Bolduc F, Boddaert N, Buckard J, Burnett H, Calvert S, Caumes R, Ng AC, Chiang D, Clifford DB, Cordelli DM, de Burca A, Demic N, Desguerre I, De Waele L, Di Fonzo A, Dunham SR, Dyack S, Elmslie F, Ferrand M, Fisher G, Karimiani EG, Ghoumid J, Gibbon F, Goel H, Hilmarsen HT, Hughes I, Jacob A, Jones EA, Kumar R, Leventer RJ, MacDonald S, Maroofian R, Mehta SG, Metz I, Monfrini E, Neumann D, Noetzel M, O'Driscoll M, Õunap K, Panzer A, Parikh S, Prabhakar P, Ramond F, Sandford R, Saneto R, Soh C, Stutterd CA, Subramanian GM, Talbot K, Thomas RH, Toro C, Touraine R, Wakeling E, Wassmer E, Whitney A, Livingston JH, O'Keefe RT, and Badrock AP
- Subjects
- Adolescent, Adult, Aged, Animals, Calcinosis complications, Calcinosis pathology, Child, Child, Preschool, Consanguinity, Disease Models, Animal, Female, Heterozygote, Humans, Infant, Infant, Newborn, Leukoencephalopathies complications, Leukoencephalopathies pathology, Male, Middle Aged, Pathology, Molecular, Young Adult, Zebrafish genetics, Calcinosis genetics, Genetic Association Studies, Leukoencephalopathies genetics, RNA, Small Nucleolar genetics
- Abstract
Biallelic mutations in SNORD118, encoding the small nucleolar RNA U8, cause leukoencephalopathy with calcifications and cysts (LCC). Given the difficulty in interpreting the functional consequences of variants in nonprotein encoding genes, and the high allelic polymorphism across SNORD118 in controls, we set out to provide a description of the molecular pathology and clinical spectrum observed in a cohort of patients with LCC. We identified 64 affected individuals from 56 families. Age at presentation varied from 3 weeks to 67 years, with disease onset after age 40 years in eight patients. Ten patients had died. We recorded 44 distinct, likely pathogenic, variants in SNORD118. Fifty two of 56 probands were compound heterozygotes, with parental consanguinity reported in only three families. Forty nine of 56 probands were either heterozygous (46) or homozygous (three) for a mutation involving one of seven nucleotides that facilitate a novel intramolecular interaction between the 5' end and 3' extension of precursor-U8. There was no obvious genotype-phenotype correlation to explain the marked variability in age at onset. Complementing recently published functional analyses in a zebrafish model, these data suggest that LCC most often occurs due to combinatorial severe and milder mutations, with the latter mostly affecting 3' end processing of precursor-U8., (© 2020 Wiley Periodicals LLC.)
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- 2021
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30. cGAS-mediated induction of type I interferon due to inborn errors of histone pre-mRNA processing.
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Uggenti C, Lepelley A, Depp M, Badrock AP, Rodero MP, El-Daher MT, Rice GI, Dhir S, Wheeler AP, Dhir A, Albawardi W, Frémond ML, Seabra L, Doig J, Blair N, Martin-Niclos MJ, Della Mina E, Rubio-Roldán A, García-Pérez JL, Sproul D, Rehwinkel J, Hertzog J, Boland-Auge A, Olaso R, Deleuze JF, Baruteau J, Brochard K, Buckley J, Cavallera V, Cereda C, De Waele LMH, Dobbie A, Doummar D, Elmslie F, Koch-Hogrebe M, Kumar R, Lamb K, Livingston JH, Majumdar A, Lorenço CM, Orcesi S, Peudenier S, Rostasy K, Salmon CA, Scott C, Tonduti D, Touati G, Valente M, van der Linden H Jr, Van Esch H, Vermelle M, Webb K, Jackson AP, Reijns MAM, Gilbert N, and Crow YJ
- Subjects
- Autoimmune Diseases of the Nervous System genetics, Autoimmune Diseases of the Nervous System immunology, Cell Line, DNA immunology, Gene Expression Regulation genetics, Gene Expression Regulation immunology, HCT116 Cells, HEK293 Cells, Hereditary Autoinflammatory Diseases genetics, Hereditary Autoinflammatory Diseases immunology, Humans, Membrane Proteins metabolism, Nervous System Malformations genetics, Nervous System Malformations immunology, Nucleotides, Cyclic biosynthesis, Nucleotidyltransferases metabolism, Chromatin metabolism, Histones metabolism, Interferon Type I biosynthesis, RNA Precursors metabolism, RNA-Binding Proteins genetics, Ribonucleoprotein, U7 Small Nuclear genetics
- Abstract
Inappropriate stimulation or defective negative regulation of the type I interferon response can lead to autoinflammation. In genetically uncharacterized cases of the type I interferonopathy Aicardi-Goutières syndrome, we identified biallelic mutations in LSM11 and RNU7-1, which encode components of the replication-dependent histone pre-mRNA-processing complex. Mutations were associated with the misprocessing of canonical histone transcripts and a disturbance of linker histone stoichiometry. Additionally, we observed an altered distribution of nuclear cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) and enhanced interferon signaling mediated by the cGAS-stimulator of interferon genes (STING) pathway in patient-derived fibroblasts. Finally, we established that chromatin without linker histone stimulates cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) production in vitro more efficiently. We conclude that nuclear histones, as key constituents of chromatin, are essential in suppressing the immunogenicity of self-DNA.
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- 2020
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31. JAK Inhibition in the Aicardi-Goutières Syndrome.
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Neven B, Al Adba B, Hully M, Desguerre I, Pressiat C, Boddaert N, Duffy D, Rice GI, Seabra L, Frémond ML, Blanche S, and Crow YJ
- Subjects
- Humans, Janus Kinases, Autoimmune Diseases of the Nervous System, Nervous System Malformations genetics
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- 2020
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32. Mutations in COPA lead to abnormal trafficking of STING to the Golgi and interferon signaling.
- Author
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Lepelley A, Martin-Niclós MJ, Le Bihan M, Marsh JA, Uggenti C, Rice GI, Bondet V, Duffy D, Hertzog J, Rehwinkel J, Amselem S, Boulisfane-El Khalifi S, Brennan M, Carter E, Chatenoud L, Chhun S, Coulomb l'Hermine A, Depp M, Legendre M, Mackenzie KJ, Marey J, McDougall C, McKenzie KJ, Molina TJ, Neven B, Seabra L, Thumerelle C, Wislez M, Nathan N, Manel N, Crow YJ, and Frémond ML
- Subjects
- Adolescent, Adult, Child, Endoplasmic Reticulum metabolism, Female, Gene Knockout Techniques, HEK293 Cells, Humans, Male, Membrane Proteins genetics, Middle Aged, Protein Transport genetics, THP-1 Cells, Transfection, Young Adult, Coatomer Protein genetics, Coatomer Protein metabolism, Golgi Apparatus metabolism, Interferon Type I metabolism, Membrane Proteins metabolism, Mutation, Missense, Signal Transduction genetics
- Abstract
Heterozygous missense mutations in coatomer protein subunit α, COPA, cause a syndrome overlapping clinically with type I IFN-mediated disease due to gain-of-function in STING, a key adaptor of IFN signaling. Recently, increased levels of IFN-stimulated genes (ISGs) were described in COPA syndrome. However, the link between COPA mutations and IFN signaling is unknown. We observed elevated levels of ISGs and IFN-α in blood of symptomatic COPA patients. In vitro, both overexpression of mutant COPA and silencing of COPA induced STING-dependent IFN signaling. We detected an interaction between COPA and STING, and mutant COPA was associated with an accumulation of ER-resident STING at the Golgi. Given the known role of the coatomer protein complex I, we speculate that loss of COPA function leads to enhanced type I IFN signaling due to a failure of Golgi-to-ER STING retrieval. These data highlight the importance of the ER-Golgi axis in the control of autoinflammation and inform therapeutic strategies in COPA syndrome., Competing Interests: Disclosures: M. Wislez reported personal fees from Boeringher Ingelheim, Roche, MSD, BMS, Astra Zeneca, and Amgen outside the submitted work. Y.J. Crow reported "other" from Biogen outside the submitted work. No other disclosures were reported., (© 2020 Lepelley et al.)
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- 2020
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33. Expanding the clinical spectrum of Fowler syndrome: Three siblings with survival into adulthood and systematic review of the literature.
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De Luca C, Crow YJ, Rodero M, Rice GI, Ahmed M, Lammens M, De Cock P, Van Esch H, Lagae L, and Rochtus A
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- Brain metabolism, Brain pathology, Genetic Association Studies, Humans, Hydranencephaly pathology, Mutation genetics, Neovascularization, Pathologic pathology, Phenotype, Hydranencephaly genetics, Membrane Transport Proteins genetics, Neovascularization, Pathologic genetics, Receptors, Virus genetics
- Abstract
Proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome (PVHH, OMIM 225790), also known as Fowler syndrome, is a rare autosomal recessive disorder of brain angiogenesis. PVHH has long been considered to be prenatally lethal. We evaluated the phenotypes of the first three siblings with survival into adulthood, performed a systematic review of the Fowler syndrome literature and delineated genotype-phenotype correlations using a scoring system to rate the severity of the disease. Thirty articles were included, describing 69 individual patients. To date, including our clinical reports, 72 patients have been described with Fowler syndrome. Only 6/72 (8%) survived beyond birth. Although our three patients carry the same mutations (c.327T>A-p.Asn109Lys and c.887C>T-p.Ser296Leu) in FLVCR2, only two of them presented with the same cerebral features, ventriculomegaly and cerebral calcifications, as affected fetuses. The third sibling has a surprisingly milder clinical and radiological phenotype, suggesting intrafamilial variability. Although no clear phenotype-genotype correlation exists, some variants appear to be associated with a less severe phenotype compatible with life. As such, it is important to consider Fowler syndrome in patients with gross ventriculomegaly, cortical malformations and/or cerebral calcifications on brain imaging., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
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- 2020
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34. Anti-MDA5 juvenile idiopathic inflammatory myopathy: a specific subgroup defined by differentially enhanced interferon-α signalling.
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Melki I, Devilliers H, Gitiaux C, Bondet V, Duffy D, Charuel JL, Miyara M, Bokov P, Kheniche A, Kwon T, Authier FJ, Allenbach Y, Belot A, Bodemer C, Bourrat E, Dumaine C, Fabien N, Faye A, Frémond ML, Hadchouel A, Kitabayashi N, Lepelley A, Martin-Niclos MJ, Mudumba S, Musset L, Quartier P, Rice GI, Seabra L, Uettwiller F, Uggenti C, Viel S, Rodero MP, Crow YJ, and Bader-Meunier B
- Subjects
- Adolescent, Child, Child, Preschool, Female, Humans, Male, Muscle, Skeletal immunology, Muscle, Skeletal pathology, Myositis immunology, Myositis pathology, Prospective Studies, Retrospective Studies, Autoantibodies immunology, Interferon-Induced Helicase, IFIH1 immunology, Interferon-alpha metabolism, Muscle, Skeletal metabolism, Myositis metabolism, Signal Transduction physiology
- Abstract
Objectives: JDM and juvenile overlap myositis represent heterogeneous subtypes of juvenile idiopathic inflammatory myopathy (JIIM). Chronic evolution can occur in up to 60% of cases, and morbidity/mortality is substantial. We aimed to describe the clinical, biological, histological and type I IFN status in JIIM associated with anti-melanoma differentiation-associated protein 5 (anti-MDA5) autoantibodies at presentation (group 1) in comparison with other JIIM (group 2)., Methods: This was a retrospective and prospective study of patients with JIIM ascertained from three French paediatric rheumatology reference centres between 2013 and 2019. Muscle biopsies were reviewed. Type I interferon pathway activity was assessed by dosage of IFNα serum protein and the expression of IFN-stimulated genes., Results: Sixty-four patients were included, 13 in group 1 (54% JDM and 46% juvenile overlap myositis) and 51 in group 2 (76% JDM and 24% juvenile overlap myositis). Group 1 patients demonstrated more arthritis, skin ulcerations, lupus features and interstitial lung disease, and a milder muscular involvement. Serum IFNα levels were higher in group 1 than 2, and decreased after treatment or improvement in both groups. Outcome was similar in both groups. Unconventional treatment (more than two lines) was required in order to achieve remission, especially when skin ulceration was reported., Conclusion: This study indicates a higher frequency of arthritis, skin ulcerations and interstitial lung disease, but milder muscular involvement, in JIIM with positive anti-MDA5 autoantibodies compared with other JIIM. Our data support an important role of systemic IFNα in disease pathology, particularly in the anti-MDA5 auto-antibody-positive subgroup. In severe and refractory forms of JIIM, IFNα may represent a therapeutic target., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
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- 2020
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35. Cardiac valve involvement in ADAR -related type I interferonopathy.
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Crow Y, Keshavan N, Barbet JP, Bercu G, Bondet V, Boussard C, Dedieu N, Duffy D, Hully M, Giardini A, Gitiaux C, Rice GI, Seabra L, Bader-Meunier B, and Rahman S
- Subjects
- Adolescent, Autoimmune Diseases of the Nervous System physiopathology, Child, Echocardiography, Female, Fibrosis genetics, Fibrosis pathology, Gain of Function Mutation, Genetic Predisposition to Disease, Heart Valve Diseases physiopathology, Heart Valves pathology, Humans, Male, Nervous System Malformations physiopathology, Phenotype, Vascular Calcification genetics, Vascular Calcification pathology, Adenosine Deaminase genetics, Autoimmune Diseases of the Nervous System genetics, Heart Valve Diseases genetics, Interferon Type I genetics, Interferon-Induced Helicase, IFIH1 genetics, Nervous System Malformations genetics, RNA-Binding Proteins genetics
- Abstract
Background: Adenosine deaminases acting on RNA ( ADAR ) mutations cause a spectrum of neurological phenotypes ranging from severe encephalopathy (Aicardi-Goutières syndrome) to isolated spastic paraplegia and are associated with enhanced type I interferon signalling. In children, non-neurological involvement in the type I interferonopathies includes autoimmune and rheumatological phenomena, with calcifying cardiac valve disease only previously reported in the context of MDA5 gain-of-function., Results: We describe three patients with biallelic ADAR mutations who developed calcifying cardiac valvular disease in late childhood (9.5-14 years). Echocardiography revealed progressive calcification of the valvular leaflets resulting in valvular stenosis and incompetence. Two patients became symptomatic with biventricular failure after 5-6.5 years. In one case, disease progressed to severe cardiac failure despite maximal medical management, with death occurring at 17 years. Another child received mechanical mitral and aortic valve replacement at 16 years with good postoperative outcome. Histological examination of the affected valves showed fibrosis and calcification., Conclusions: Type I interferonopathies of differing genetic aetiology demonstrate an overlapping phenotypic spectrum which includes calcifying cardiac valvular disease. Individuals with ADAR -related type I interferonopathy may develop childhood-onset multivalvular stenosis and incompetence which can progress insidiously to symptomatic, and ultimately fatal, cardiac failure. Regular surveillance echocardiograms are recommended to detect valvular disease early., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2020
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36. Clinical Reasoning: A 25-year-old woman with recurrent episodes of collapse and loss of consciousness.
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Wildman J, Baker MR, Price DA, Tiwari S, Kumar H, Rice GI, Crow YJ, and Thomas RH
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- Adult, Calcinosis physiopathology, Central Nervous System Cysts physiopathology, Diagnosis, Differential, Female, Humans, Leukoencephalopathies physiopathology, Recurrence, Seizures physiopathology, Unconsciousness physiopathology, Calcinosis complications, Calcinosis diagnostic imaging, Central Nervous System Cysts complications, Central Nervous System Cysts diagnostic imaging, Leukoencephalopathies complications, Leukoencephalopathies diagnostic imaging, Seizures diagnostic imaging, Seizures etiology, Unconsciousness diagnostic imaging, Unconsciousness etiology
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- 2020
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37. Biallelic Mutations in MTPAP Associated with a Lethal Encephalopathy.
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Van Eyck L, Bruni F, Ronan A, Briggs TA, Roscioli T, Rice GI, Vassallo G, Rodero MP, He L, Taylor RW, Livingston JH, Chrzanowska-Lightowlers ZMA, and Crow YJ
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- Female, Humans, Infant, Infant Death, Male, Mitochondrial Proteins genetics, Pedigree, Exome Sequencing, Brain Diseases genetics, Brain Diseases metabolism, DNA-Directed RNA Polymerases genetics, Fibroblasts metabolism, Mitochondrial Proteins metabolism
- Abstract
Background: A homozygous founder mutation in MTPAP / TENT6 , encoding mitochondrial poly(A) polymerase (MTPAP), was first reported in six individuals of Old Order Amish descent demonstrating an early-onset, progressive spastic ataxia with optic atrophy and learning difficulties. MTPAP contributes to the regulation of mitochondrial gene expression through the polyadenylation of mitochondrially encoded mRNAs. Mitochondrial mRNAs with severely truncated poly(A) tails were observed in affected individuals, and mitochondrial protein expression was altered., Objective: To determine the genetic basis of a perinatal encephalopathy associated with stereotyped neuroimaging and infantile death in three patients from two unrelated families., Methods: Whole-exome sequencing was performed in two unrelated patients and the unaffected parents of one of these individuals. Variants and familial segregation were confirmed by Sanger sequencing. Polyadenylation of mitochondrial transcripts and de novo synthesis of mitochondrial proteins were assessed in patient's fibroblasts., Results: Compound heterozygous p.Ile428Thr and p.Arg523Trp substitutions in MTPAP were recorded in two affected siblings from one family, and a homozygous p.Ile385Phe missense variant identified in a further affected child from a second sibship. Mitochondrial poly(A) tail analysis demonstrated shorter posttranscriptional additions to the mitochondrial transcripts, as well as an altered expression of mitochondrial proteins in the fibroblasts of the two siblings compared with healthy controls., Conclusion: Mutations in MTPAP likely cause an autosomal recessive perinatal encephalopathy with lethality in the first year of life., Competing Interests: None., (Georg Thieme Verlag KG Stuttgart · New York.)
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- 2020
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38. Type 1 interferonopathy presenting as juvenile idiopathic arthritis with interstitial lung disease: report of a new phenotype.
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Clarke SLN, Robertson L, Rice GI, Seabra L, Hilliard TN, Crow YJ, and Ramanan AV
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- Adolescent, Arthritis, Juvenile drug therapy, Arthritis, Juvenile immunology, Azetidines therapeutic use, Family, Female, Glucocorticoids therapeutic use, Hereditary Autoinflammatory Diseases drug therapy, Hereditary Autoinflammatory Diseases genetics, Hereditary Autoinflammatory Diseases immunology, Heterozygote, Humans, Immunoglobulins, Intravenous therapeutic use, Immunologic Factors therapeutic use, Infant, Infant, Newborn, Interferon Type I immunology, Janus Kinase Inhibitors therapeutic use, Lung Diseases, Interstitial drug therapy, Lung Diseases, Interstitial immunology, Mutation, Phenotype, Purines therapeutic use, Pyrazoles therapeutic use, Sulfonamides therapeutic use, Syndrome, Vascular Diseases drug therapy, Vascular Diseases genetics, Vascular Diseases immunology, Arthritis, Juvenile physiopathology, Hereditary Autoinflammatory Diseases physiopathology, Lung Diseases, Interstitial physiopathology, Membrane Proteins genetics, Vascular Diseases physiopathology
- Abstract
Background: STING-associated vasculopathy with onset in infancy (SAVI) is a type 1 interferonopathy manifesting as a pulmonary and vascular syndrome resulting from gain-of-function mutations in TMEM173, the gene encoding STING. Familial reports in the literature are sparse., Case Presentation: We report a case series of SAVI in a three generation kindred, with a phenotype of interstitial lung disease (ILD) and rheumatoid factor positive polyarticular juvenile idiopathic arthritis (JIA). Current and historical medical records were reviewed for clinical and laboratory information. Whole blood from cases 1 and 2, plus stored appendicectomy tissue from case 3, underwent DNA sequencing of the TMEM173 gene. Peripheral blood RNA was obtained from cases 1 and 2 for functional assessment of the TMEM173 mutation. DNA sequencing identified the same heterozygous TMEM173 mutation (c.463G > A; p.Val155Met) in all three cases, consistent with a diagnosis of the autosomal dominant condition SAVI. Functional assessment of this mutation identified a prominent interferon signature which was confirmed on repeat testing., Conclusions: SAVI presented in this family as ILD with early onset juvenile rheumatoid arthritis. This condition should be considered in all rheumatoid arthritis patients with early-onset ILD and in all JIA patients with ILD.
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- 2020
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39. Analysis of U8 snoRNA Variants in Zebrafish Reveals How Bi-allelic Variants Cause Leukoencephalopathy with Calcifications and Cysts.
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Badrock AP, Uggenti C, Wacheul L, Crilly S, Jenkinson EM, Rice GI, Kasher PR, Lafontaine DLJ, Crow YJ, and O'Keefe RT
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- Animals, Base Sequence, Calcinosis pathology, Central Nervous System Cysts pathology, Conserved Sequence, Disease Models, Animal, Embryonic Development genetics, Humans, Leukoencephalopathies pathology, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism, Zebrafish embryology, Zebrafish Proteins genetics, Zebrafish Proteins metabolism, Alleles, Calcinosis genetics, Central Nervous System Cysts genetics, Cysts genetics, Leukoencephalopathies genetics, Mutation, RNA, Small Nucleolar genetics, Zebrafish genetics
- Abstract
How mutations in the non-coding U8 snoRNA cause the neurological disorder leukoencephalopathy with calcifications and cysts (LCC) is poorly understood. Here, we report the generation of a mutant U8 animal model for interrogating LCC-associated pathology. Mutant U8 zebrafish exhibit defective central nervous system development, a disturbance of ribosomal RNA (rRNA) biogenesis and tp53 activation, which monitors ribosome biogenesis. Further, we demonstrate that fibroblasts from individuals with LCC are defective in rRNA processing. Human precursor-U8 (pre-U8) containing a 3' extension rescued mutant U8 zebrafish, and this result indicates conserved biological function. Analysis of LCC-associated U8 mutations in zebrafish revealed that one null and one functional allele contribute to LCC. We show that mutations in three nucleotides at the 5' end of pre-U8 alter the processing of the 3' extension, and we identify a previously unknown base-pairing interaction between the 5' end and the 3' extension of human pre-U8. Indeed, LCC-associated mutations in any one of seven nucleotides in the 5' end and 3' extension alter the processing of pre-U8, and these mutations are present on a single allele in almost all individuals with LCC identified to date. Given genetic data indicating that bi-allelic null U8 alleles are likely incompatible with human development, and that LCC is not caused by haploinsufficiency, the identification of hypomorphic misprocessing mutations that mediate viable embryogenesis furthers our understanding of LCC molecular pathology and cerebral vascular homeostasis., (Copyright © 2020 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
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- 2020
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40. Biallelic mutations in NRROS cause an early onset lethal microgliopathy.
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Smith C, McColl BW, Patir A, Barrington J, Armishaw J, Clarke A, Eaton J, Hobbs V, Mansour S, Nolan M, Rice GI, Rodero MP, Seabra L, Uggenti C, Livingston JH, Bridges LR, Jeffrey IJM, and Crow YJ
- Subjects
- Age of Onset, Alleles, Animals, Female, Humans, Male, Mice, Knockout, Pedigree, Brain pathology, Latent TGF-beta Binding Proteins genetics, Mutation genetics
- Published
- 2020
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41. Genetic and phenotypic spectrum associated with IFIH1 gain-of-function.
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Rice GI, Park S, Gavazzi F, Adang LA, Ayuk LA, Van Eyck L, Seabra L, Barrea C, Battini R, Belot A, Berg S, Billette de Villemeur T, Bley AE, Blumkin L, Boespflug-Tanguy O, Briggs TA, Brimble E, Dale RC, Darin N, Debray FG, De Giorgis V, Denecke J, Doummar D, Drake Af Hagelsrum G, Eleftheriou D, Estienne M, Fazzi E, Feillet F, Galli J, Hartog N, Harvengt J, Heron B, Heron D, Kelly DA, Lev D, Levrat V, Livingston JH, Marti I, Mignot C, Mochel F, Nougues MC, Oppermann I, Pérez-Dueñas B, Popp B, Rodero MP, Rodriguez D, Saletti V, Sharpe C, Tonduti D, Vadlamani G, Van Haren K, Tomas Vila M, Vogt J, Wassmer E, Wiedemann A, Wilson CJ, Zerem A, Zweier C, Zuberi SM, Orcesi S, Vanderver AL, Hur S, and Crow YJ
- Subjects
- Alleles, Autoimmune Diseases of the Nervous System diagnosis, Autoimmune Diseases of the Nervous System genetics, DNA Mutational Analysis, Female, High-Throughput Nucleotide Sequencing, Humans, Interferon-Induced Helicase, IFIH1 chemistry, Male, Models, Molecular, Nervous System Malformations diagnosis, Nervous System Malformations genetics, Protein Conformation, Structure-Activity Relationship, Gain of Function Mutation, Genetic Association Studies methods, Genotype, Interferon-Induced Helicase, IFIH1 genetics, Phenotype
- Abstract
IFIH1 gain-of-function has been reported as a cause of a type I interferonopathy encompassing a spectrum of autoinflammatory phenotypes including Aicardi-Goutières syndrome and Singleton Merten syndrome. Ascertaining patients through a European and North American collaboration, we set out to describe the molecular, clinical and interferon status of a cohort of individuals with pathogenic heterozygous mutations in IFIH1. We identified 74 individuals from 51 families segregating a total of 27 likely pathogenic mutations in IFIH1. Ten adult individuals, 13.5% of all mutation carriers, were clinically asymptomatic (with seven of these aged over 50 years). All mutations were associated with enhanced type I interferon signaling, including six variants (22%) which were predicted as benign according to multiple in silico pathogenicity programs. The identified mutations cluster close to the ATP binding region of the protein. These data confirm variable expression and nonpenetrance as important characteristics of the IFIH1 genotype, a consistent association with enhanced type I interferon signaling, and a common mutational mechanism involving increased RNA binding affinity or decreased efficiency of ATP hydrolysis and filament disassembly rate., (© 2020 The Authors. Human Mutation published by Wiley Periodicals, Inc.)
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- 2020
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42. Contribution of rare and predicted pathogenic gene variants to childhood-onset lupus: a large, genetic panel analysis of British and French cohorts.
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Belot A, Rice GI, Omarjee SO, Rouchon Q, Smith EMD, Moreews M, Tusseau M, Frachette C, Bournhonesque R, Thielens N, Gaboriaud C, Rouvet I, Chopin E, Hoshino A, Latour S, Ranchin B, Cimaz R, Romagnani P, Malcus C, Fabien N, Sarda MN, Kassai B, Lega JC, Decramer S, Abou-Jaoude P, Bruce IN, Simonet T, Bardel C, Rollat-Farnier PA, Viel S, Reumaux H, O'Sullivan J, Walzer T, Mathieu AL, Marenne G, Ludwig T, Genin E, Ellingford J, Bader-Meunier B, Briggs TA, Beresford MW, and Crow YJ
- Abstract
Background: Systemic lupus erythematosus (SLE) is a rare immunological disorder and genetic factors are considered important in its causation. Monogenic lupus has been associated with around 30 genotypes in humans and 60 in mice, while genome-wide association studies have identified more than 90 risk loci. We aimed to analyse the contribution of rare and predicted pathogenic gene variants in a population of unselected cases of childhood-onset SLE., Methods: For this genetic panel analysis we designed a next-generation sequencing panel comprising 147 genes, including all known lupus-causing genes in humans, and potentially lupus-causing genes identified through GWAS and animal models. We screened 117 probands fulfilling American College of Rheumatology (ACR) criteria for SLE, ascertained through British and French cohorts of childhood-onset SLE, and compared these data with those of 791 ethnically matched controls from the 1000 Genomes Project and 574 controls from the FREX Consortium., Findings: After filtering, mendelian genotypes were confirmed in eight probands, involving variants in C1QA, C1QC, C2, DNASE1L3, and IKZF1. Seven additional patients carried heterozygous variants in complement or type I interferon-associated autosomal recessive genes, with decreased concentrations of the encoded proteins C3 and C9 recorded in two patients. Rare variants that were predicted to be damaging were significantly enriched in the childhood-onset SLE cohort compared with controls; 25% of SLE probands versus 5% of controls were identified to harbour at least one rare, predicted damaging variant (p=2·98 × 10
-11 ). Inborn errors of immunity were estimated to account for 7% of cases of childhood-onset SLE, with defects in innate immunity representing the main monogenic contribution., Interpretation: An accumulation of rare variants that are predicted to be damaging in SLE-associated genes might contribute to disease expression and clinical heterogeneity., Funding: European Research Council., (Copyright © 2020 Elsevier Ltd. All rights reserved.)- Published
- 2020
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43. Genetic polymorphism in C3 is associated with progression in chronic kidney disease (CKD) patients with IgA nephropathy but not in other causes of CKD.
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Ibrahim ST, Chinnadurai R, Ali I, Payne D, Rice GI, Newman WG, Algohary E, Adam AG, and Kalra PA
- Subjects
- Aged, Female, Gene Frequency, Heterozygote, Humans, Male, Middle Aged, Polymorphism, Genetic, Complement C3 genetics, Disease Progression, Renal Insufficiency, Chronic genetics, Renal Insufficiency, Chronic mortality
- Abstract
Objectives: The R102G variant in complement 3 (C3) results in two allotypic variants: C3 fast (C3F) and C3 slow (C3S). C3F presents at increased frequency in patients with chronic kidney disease (CKD), our aim is to explore its role in CKD progression and mortality., Methods: Delta (Δ) eGFR for 2038 patients in the Salford Kidney Study (SKS) was calculated by linear regression; those with ≤-3ml/min/1.73m2/yr were defined as rapid progressors (RP) and those with ΔeGFR between -0.5 and +1ml/min/1.73m2/yr, labelled stable CKD patients (SP).A group of 454 volunteers was used as a control group. In addition, all biopsy-proven glomerulonephritis (GN) patients were studied regardless of their ΔeGFR. R102G was analysed by real-time PCR, and genotypic and allelic frequencies were compared between RP and SP along with the healthy control group., Results: There were 255 SP and 259 RP in the final cohort. Median ΔeGFR was 0.07 vs. -4.7 ml/min/1.73m2/yr in SP vs. RP. C3F allele frequency was found to be significantly higher in our CKD cohort (25.7%) compared with the healthy control group (20.6%); p = 0.008.However, there was no significant difference in C3F allele frequency between the RP and SP groups. In a subgroup analysis of 37 patients with IgA nephropathy in the CKD cohort (21 RP and 16 SP), there was a significantly higher frequency of C3F in RP 40.5% vs. 9.4% in SP; p = 0.003. In the GN group, Cox regression showed an association between C3F and progression only in those with IgA nephropathy (n = 114);HR = 1.9 (95% CI 1.1-3.1; p = 0.018) for individuals heterozygous for the C3F variant, increased further for individuals homozygous for the variant, HR = 2.8 (95% CI 1.2-6.2; p = 0.014)., Conclusion: The C3 variant R102G is associated with progression of CKD in patients with IgA nephropathy., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2020
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44. Use of ruxolitinib in COPA syndrome manifesting as life-threatening alveolar haemorrhage.
- Author
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Frémond ML, Legendre M, Fayon M, Clement A, Filhol-Blin E, Richard N, Berdah L, Roullaud S, Rice GI, Bondet V, Duffy D, Sileo C, Ducou le Pointe H, Begueret H, Coulomb A, Neven B, Amselem S, Crow Y, and Nathan N
- Subjects
- Child, Female, Hemosiderosis genetics, Humans, Lung Diseases genetics, Nitriles, Pyrimidines, Hemosiderosis, Pulmonary, Hemorrhage drug therapy, Hemosiderosis drug therapy, Lung Diseases drug therapy, Pyrazoles therapeutic use
- Abstract
COPA (coatomer subunit α) syndrome is a newly recognised cause of interstitial lung disease in children and adults, frequently associated with arthritis and renal dysfunction. We report a 11-year-old girl with disease limited to major pulmonary haemosiderosis manifesting at the age of 2 years, due to a heterozygous p.(Arg233His) mutation in COPA Her interferon (IFN) signature was elevated (10.312 and 12.429, healthy <2.466), as was the level of serum IFNα (211 fg/mL, healthy <10 fg/mL). STAT1 phosphorylation in T lymphocytes and monocytes was increased as compared with healthy controls. Based on these results she was treated with the JAK1/2 inhibitor ruxolitinib, which resulted in reduction in IFN signalling and appeared to be associated with partial though incomplete decrease in the severity of her pulmonary disease. Patients with alveolar haemorrhage of unknown origin should be considered for COPA screening. Functional tests can help to personalise patient therapy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2020
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45. Severe type I interferonopathy and unrestrained interferon signaling due to a homozygous germline mutation in STAT2 .
- Author
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Duncan CJA, Thompson BJ, Chen R, Rice GI, Gothe F, Young DF, Lovell SC, Shuttleworth VG, Brocklebank V, Corner B, Skelton AJ, Bondet V, Coxhead J, Duffy D, Fourrage C, Livingston JH, Pavaine J, Cheesman E, Bitetti S, Grainger A, Acres M, Innes BA, Mikulasova A, Sun R, Hussain R, Wright R, Wynn R, Zarhrate M, Zeef LAH, Wood K, Hughes SM, Harris CL, Engelhardt KR, Crow YJ, Randall RE, Kavanagh D, Hambleton S, and Briggs TA
- Subjects
- Germ-Line Mutation, Humans, Immune System Diseases immunology, Infant, Male, Signal Transduction, Immune System Diseases genetics, Interferon Type I immunology, STAT2 Transcription Factor genetics
- Abstract
Excessive type I interferon (IFNα/β) activity is implicated in a spectrum of human disease, yet its direct role remains to be conclusively proven. We investigated two siblings with severe early-onset autoinflammatory disease and an elevated IFN signature. Whole-exome sequencing revealed a shared homozygous missense Arg148Trp variant in STAT2 , a transcription factor that functions exclusively downstream of innate IFNs. Cells bearing STAT2
R148W in homozygosity (but not heterozygosity) were hypersensitive to IFNα/β, which manifest as prolonged Janus kinase-signal transducers and activators of transcription (STAT) signaling and transcriptional activation. We show that this gain of IFN activity results from the failure of mutant STAT2R148W to interact with ubiquitin-specific protease 18, a key STAT2-dependent negative regulator of IFNα/β signaling. These observations reveal an essential in vivo function of STAT2 in the regulation of human IFNα/β signaling, providing concrete evidence of the serious pathological consequences of unrestrained IFNα/β activity and supporting efforts to target this pathway therapeutically in IFN-associated disease., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)- Published
- 2019
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46. Complexity in unclassified auto-inflammatory disease: a case report illustrating the potential for disease arising from the allelic burden of multiple variants.
- Author
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Tucker LB, Lamot L, Niemietz I, Chung BK, Cabral DA, Houghton K, Petty RE, Morishita KA, Rice GI, Turvey SE, Gibson WT, and Brown KL
- Subjects
- Adolescent, Anti-Inflammatory Agents therapeutic use, Antibodies, Monoclonal, Humanized therapeutic use, Collagen Type VI genetics, Cytokines blood, Cytokines cerebrospinal fluid, Fever etiology, Genetic Variation genetics, Hereditary Autoinflammatory Diseases diagnosis, Hereditary Autoinflammatory Diseases pathology, Humans, Intracellular Signaling Peptides and Proteins genetics, Karyotyping, Male, Microtubule Proteins genetics, Receptors, Immunologic genetics, Whole Genome Sequencing, Hereditary Autoinflammatory Diseases genetics
- Abstract
Background: Despite recent advances in the diagnosis and understanding of many autoinflammatory diseases, there are still a great number of patients with phenotypes that do not fit any clinically- and/or genetically-defined disorders., Case Presentation: We describe a fourteen-year-old boy who presented at two and a half years of age with recurrent febrile episodes. Over the course of the disease, the episodes increased in frequency and severity, with new signs and symptoms continuing to appear. Most importantly, these included skin changes, splenomegaly and transaminitis. Only partial control of the disease was achieved with anti-IL-1 therapy. Extensive investigation showed generalized inflammation without immune deficiency, with increased levels of serum amyloid A and several pro-inflammatory cytokines including interferon-γ, as well as an increased type I interferon score. Exome sequence analysis identified P369S and R408Q variants in the MEFV innate immunity regulator, pyrin (MEFV) gene and T260 M and T320 M variants in the NLR family pyrin domain containing 12 (NLRP12) gene., Conclusion: Patients with unclassified and/or unexplained autoinflammatory syndromes present diagnostic and therapeutic challenges and collectively form a substantial part of every cohort of patients with autoinflammatory diseases. Therefore, it is important to acquire their full genomic profile through whole exome and/or genome sequencing and present their cases to a broader audience, to facilitate characterization of similar patients. A critical mass of well-characterized cases will lead to improved diagnosis and informed treatment.
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- 2019
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47. Comment on: 'Aberrant tRNA processing causes an autoinflammatory syndrome responsive to TNF inhibitors' by Giannelou et al : mutations in TRNT1 result in a constitutive activation of type I interferon signalling.
- Author
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Frémond ML, Melki I, Kracker S, Bondet V, Duffy D, Rice GI, Crow YJ, and Bader-Meunier B
- Subjects
- Gene Expression, Mutation, RNA, Transfer, Interferon Type I, Tumor Necrosis Factor Inhibitors
- Abstract
Competing Interests: Competing interests: None declared.
- Published
- 2019
- Full Text
- View/download PDF
48. Type I interferon in patients with systemic autoimmune rheumatic disease is associated with haematological abnormalities and specific autoantibody profiles.
- Author
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Reynolds JA, Briggs TA, Rice GI, Darmalinggam S, Bondet V, Bruce E, Khan M, Haque S, Chinoy H, Herrick AL, McCarthy EM, Zeef L, Hayes A, Duffy D, Parker B, and Bruce IN
- Subjects
- Adult, Autoantibodies immunology, Autoimmune Diseases blood, Biomarkers blood, Female, Humans, Interferon Type I immunology, Interferon-alpha blood, Interferon-alpha immunology, Male, Middle Aged, Rheumatic Diseases blood, Transcriptome genetics, Young Adult, Autoantibodies blood, Autoimmune Diseases immunology, Interferon Type I blood, Rheumatic Diseases immunology
- Abstract
Objectives: To investigate the relationships between interferon alpha (IFNα) and the clinical and serological phenotype of patients with systemic autoimmune rheumatic disease (SARDs) in order to determine whether a distinct subpopulation of patients can be identified., Methods: We recruited patients with at least 1 SARD clinical feature and at least 1 SARD-related autoantibody from two NHS Trusts in Greater Manchester. A 6-gene interferon-stimulated gene (ISG) score was calculated in all patients, and in a subgroup, a 30-gene ISG score was produced using NanoString. A digital Single Molecule Array (Simoa) was used to measure plasma IFNα protein. In an exploratory analysis, whole blood RNA sequencing was conducted in 12 patients followed by RT-qPCR confirmation of expression of 6 nucleic acid receptors (NARs) in the whole cohort., Results: Sixty three of 164 (38%) patients had a positive ISG score. The 3 measures of IFNα all correlated strongly with each other (p < 0.0001). There were no differences in mucocutaneous or internal organ involvement between the ISG subgroups. The ISG-positive group had increased frequency of specific autoantibodies and haematological abnormalities which remained significant after adjusting for the SARD subtype. Expression of DDX58, MB21D1 and TLR7 was correlated with the ISG score whilst TLR3, TLR9 and MB21D1 were associated with neutrophil count., Conclusion: In SARD patients, IFNα-positivity was associated with specific autoantibodies and haematological parameters but not with other clinical features. The variable NAR expression suggests that different pathways may drive IFNα production in individual patients. The identification of an IFNα-positive subgroup within a mixed SARD cohort supports a pathology-based approach to treatment.
- Published
- 2019
- Full Text
- View/download PDF
49. Bloom syndrome protein restrains innate immune sensing of micronuclei by cGAS.
- Author
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Gratia M, Rodero MP, Conrad C, Bou Samra E, Maurin M, Rice GI, Duffy D, Revy P, Petit F, Dale RC, Crow YJ, Amor-Gueret M, and Manel N
- Subjects
- 2',5'-Oligoadenylate Synthetase genetics, Adaptor Proteins, Signal Transducing genetics, Apoptosis Regulatory Proteins genetics, Bloom Syndrome pathology, Child, Cytosol metabolism, DNA Damage immunology, Exodeoxyribonucleases metabolism, Fibroblasts metabolism, HEK293 Cells, HeLa Cells, Humans, Interferon Regulatory Factor-3 metabolism, Male, Membrane Proteins metabolism, Nucleotidyltransferases genetics, Phosphoproteins metabolism, RNA-Binding Proteins genetics, RecQ Helicases genetics, Transcriptome, Transduction, Genetic, Tumor Suppressor Proteins genetics, Immunity, Innate immunology, Nucleotidyltransferases metabolism, RecQ Helicases immunology
- Abstract
Cellular innate immune sensors of DNA are essential for host defense against invading pathogens. However, the presence of self-DNA inside cells poses a risk of triggering unchecked immune responses. The mechanisms limiting induction of inflammation by self-DNA are poorly understood. BLM RecQ-like helicase is essential for genome integrity and is deficient in Bloom syndrome (BS), a rare genetic disease characterized by genome instability, accumulation of micronuclei, susceptibility to cancer, and immunodeficiency. Here, we show that BLM-deficient fibroblasts show constitutive up-regulation of inflammatory interferon-stimulated gene (ISG) expression, which is mediated by the cGAS-STING-IRF3 cytosolic DNA-sensing pathway. Increased DNA damage or down-regulation of the cytoplasmic exonuclease TREX1 enhances ISG expression in BLM-deficient fibroblasts. cGAS-containing cytoplasmic micronuclei are increased in BS cells. Finally, BS patients demonstrate elevated ISG expression in peripheral blood. These results reveal that BLM limits ISG induction, thus connecting DNA damage to cellular innate immune response, which may contribute to human pathogenesis., (© 2019 Gratia et al.)
- Published
- 2019
- Full Text
- View/download PDF
50. Efficacy of JAK1/2 inhibition in the treatment of chilblain lupus due to TREX1 deficiency.
- Author
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Briand C, Frémond ML, Bessis D, Carbasse A, Rice GI, Bondet V, Duffy D, Chatenoud L, Blanche S, Crow YJ, and Neven B
- Subjects
- Chilblains genetics, Child, Preschool, Female, Humans, Infant, Janus Kinase 1 antagonists & inhibitors, Janus Kinase 2 antagonists & inhibitors, Lupus Erythematosus, Cutaneous genetics, Treatment Outcome, Chilblains drug therapy, Exodeoxyribonucleases deficiency, Janus Kinase Inhibitors therapeutic use, Lupus Erythematosus, Cutaneous drug therapy, Phosphoproteins deficiency
- Abstract
Competing Interests: Competing interests: None declared.
- Published
- 2019
- Full Text
- View/download PDF
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