292 results on '"Crow YJ"'
Search Results
2. Inflammatory profiles across the spectrum of disease reveal a distinct role for GM-CSF in severe COVID-19.
- Author
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Thwaites, RS, Sanchez Sevilla Uruchurtu, A, Siggins, MK, Liew, F, Russell, CD, Moore, SC, Fairfield, C, Carter, E, Abrams, S, Short, C-E, Thaventhiran, T, Bergstrom, E, Gardener, Z, Ascough, S, Chiu, C, Docherty, AB, Hunt, D, Crow, YJ, Solomon, T, Taylor, GP, Turtle, L, Harrison, EM, Dunning, J, Semple, MG, Baillie, JK, Openshaw, PJ, ISARIC4C investigators, Thwaites, RS, Sanchez Sevilla Uruchurtu, A, Siggins, MK, Liew, F, Russell, CD, Moore, SC, Fairfield, C, Carter, E, Abrams, S, Short, C-E, Thaventhiran, T, Bergstrom, E, Gardener, Z, Ascough, S, Chiu, C, Docherty, AB, Hunt, D, Crow, YJ, Solomon, T, Taylor, GP, Turtle, L, Harrison, EM, Dunning, J, Semple, MG, Baillie, JK, Openshaw, PJ, and ISARIC4C investigators
- Abstract
While it is now widely accepted that host inflammatory responses contribute to lung injury, the pathways that drive severity and distinguish coronavirus disease 2019 (COVID-19) from other viral lung diseases remain poorly characterized. We analyzed plasma samples from 471 hospitalized patients recruited through the prospective multicenter ISARIC4C study and 39 outpatients with mild disease, enabling extensive characterization of responses across a full spectrum of COVID-19 severity. Progressive elevation of levels of numerous inflammatory cytokines and chemokines (including IL-6, CXCL10, and GM-CSF) were associated with severity and accompanied by elevated markers of endothelial injury and thrombosis. Principal component and network analyses demonstrated central roles for IL-6 and GM-CSF in COVID-19 pathogenesis. Comparing these profiles to archived samples from patients with fatal influenza, IL-6 was equally elevated in both conditions whereas GM-CSF was prominent only in COVID-19. These findings further identify the key inflammatory, thrombotic, and vascular factors that characterize and distinguish severe and fatal COVID-19.
- Published
- 2021
3. Leukoencephalopathy with calcifications and cysts: Genetic and phenotypic spectrum
- Author
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Crow, YJ, Marshall, H, Rice, G, 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-H, Chiang, D, Clifford, DB, Cordelli, DM, 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, Ounap, 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, Badrock, AP, Crow, YJ, Marshall, H, Rice, G, 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-H, Chiang, D, Clifford, DB, Cordelli, DM, 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, Ounap, 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
- 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.
- Published
- 2020
4. The 2017 IUIS Phenotypic Classification for Primary Immunodeficiencies
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Bousfiha, A, Jeddane, L, Picard, C, Ailal, F, Gaspar, HB, Al-Herz, W, Chatila, T, Crow, YJ, Cunningham-Rundles, C, Etzioni, A, Luis Franco, J, Holland, SM, Klein, C, Morio, T, Ochs, HD, Oksenhendler, E, Puck, J, Tang, MLK, Tangye, SG, Torgerson, TR, Casanova, J-L, Sullivan, KE, Bousfiha, A, Jeddane, L, Picard, C, Ailal, F, Gaspar, HB, Al-Herz, W, Chatila, T, Crow, YJ, Cunningham-Rundles, C, Etzioni, A, Luis Franco, J, Holland, SM, Klein, C, Morio, T, Ochs, HD, Oksenhendler, E, Puck, J, Tang, MLK, Tangye, SG, Torgerson, TR, Casanova, J-L, and Sullivan, KE
- Abstract
Since the 1990s, the International Union of Immunological Societies (IUIS) PID expert committee (EC), now called Inborn Errors of Immunity Committee, has published every other year a classification of the inborn errors of immunity. This complete catalog serves as a reference for immunologists and researchers worldwide. However, it was unadapted for clinicians at the bedside. For those, the IUIS PID EC is now publishing a phenotypical classification since 2013, which proved to be more user-friendly. There are now 320 single-gene inborn errors of immunity underlying phenotypes as diverse as infection, malignancy, allergy, auto-immunity, and auto-inflammation. We herein propose the revised 2017 phenotypic classification, based on the accompanying 2017 IUIS Inborn Errors of Immunity Committee classification.
- Published
- 2018
5. International Union of Immunological Societies: 2017 Primary Immunodeficiency Diseases Committee Report on Inborn Errors of Immunity
- Author
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Picard, C, Bobby Gaspar, H, Al-Herz, W, Bousfiha, A, Casanova, J-L, Chatila, T, Crow, YJ, Cunningham-Rundles, C, Etzioni, A, Luis Franco, J, Holland, SM, Klein, C, Morio, T, Ochs, HD, Oksenhendler, E, Puck, J, Tang, MLK, Tangye, SG, Torgerson, TR, Sullivan, KE, Picard, C, Bobby Gaspar, H, Al-Herz, W, Bousfiha, A, Casanova, J-L, Chatila, T, Crow, YJ, Cunningham-Rundles, C, Etzioni, A, Luis Franco, J, Holland, SM, Klein, C, Morio, T, Ochs, HD, Oksenhendler, E, Puck, J, Tang, MLK, Tangye, SG, Torgerson, TR, and Sullivan, KE
- Abstract
Beginning in 1970, a committee was constituted under the auspices of the World Health Organization (WHO) to catalog primary immunodeficiencies. Twenty years later, the International Union of Immunological Societies (IUIS) took the remit of this committee. The current report details the categorization and listing of 354 (as of February 2017) inborn errors of immunity. The growth and increasing complexity of the field have been impressive, encompassing an increasing variety of conditions, and the classification described here will serve as a critical reference for immunologists and researchers worldwide.
- Published
- 2018
6. THU0528 Sting-associated vasculopathy with onset in infancy (SAVI): a differential diagnosis of inflammatory interstitial lung disease
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Dagher, R, primary, Ghiye, R, additional, Nicolas, G, additional, Feghali, H, additional, Khalife, MC Fadous, additional, Seabra, L, additional, and Crow, YJ, additional
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- 2017
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7. Human USP18 deficiency underlies type 1 interferonopathy leading to severe pseudo-TOR CH syndrome
- Author
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Meuwissen, Marije, Schot, Rachel, Buta, S, Oudesluijs, Grietje, Tinschert, S, Speer, SD, Li, Z, Unen, Leontine, Heijsman, Daphne, Goldmann, T, Lequin, MH, Kros, J.M., Stam, W (Wendy), Hermann, M, Willemsen, Rob, Brouwer, Rutger, van Ijcken, Wilfred, Martin-Fernandez, M, Coo, IFM, Dudink, J, Vries, Femke, Bertoli Avella, AM, Prinz, M, Crow, YJ, Verheijen, Frans, Pellegrini, S, Bogunovic, D, Verheijen - Mancini, Grazia, Meuwissen, Marije, Schot, Rachel, Buta, S, Oudesluijs, Grietje, Tinschert, S, Speer, SD, Li, Z, Unen, Leontine, Heijsman, Daphne, Goldmann, T, Lequin, MH, Kros, J.M., Stam, W (Wendy), Hermann, M, Willemsen, Rob, Brouwer, Rutger, van Ijcken, Wilfred, Martin-Fernandez, M, Coo, IFM, Dudink, J, Vries, Femke, Bertoli Avella, AM, Prinz, M, Crow, YJ, Verheijen, Frans, Pellegrini, S, Bogunovic, D, and Verheijen - Mancini, Grazia
- Published
- 2016
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, 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
9. Gain of function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling
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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
10. Aicardi-Goutières Syndrome of neonatal onset simulating a congenital infection
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Esteban-Marfil, MV, Martínez-Espinosa, N, Santiago-Gutiérrez, C, Sierra-Córcoles, C, Cruz-Moreno, J de la, Sanchís-Calvo, A, Crow, YJ, and Martínez-Frías, ML
- Abstract
Dismorfología y Genética Clínica Aicardi-Goutières Syndrome (AGS) is a genetic disorder with autosomal recessive aetiology characterized by an early developed encephalopathy with severe physical and mental handicaps. The neonatal form (20% of the cases) shows a phenotype similar to a congenital infection, hence there exists the possibility of misdiagnosis and misinformation to parents about the risk of recurrence. We present a new case of AGS with a neonatal onset and also review clinical patterns, laboratory and neuroimaging findings, and new advances in geneticmolecular diagnosis that have allowed us to delineate the phenotypic spectrum and confirm the aetiology in more than 80% of cases. No
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- 2009
11. Aicardi-Goutières syndrome presenting atypically as a sub-acute leukoencephalopathy
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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.
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- 2008
12. Infection-triggered familial or recurrent cases of acute necrotizing encephalopathy caused by mutations in a component of the nuclear pore, RANBP2
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Neilson, De, Adams, Md, Orr, Cmd, Schelling, Dk, Eiben, Rm, Kerr, D, Anderson, J, Bassuk, Ag, Bye, Am, Childs, A, Clarke, A, Crow, Yj, Di Rocco, M, Dohna Schwake, C, Dueckers, G, Fasano, Ae, Gika, Ad, Gionnis, D, Gorman, Mp, Grattan Smith, Pj, Hackenberg, A, Kuster, A, Lentschig, Mg, Lopez Laso, E, Marco, Ej, Mastroyianni, S, Perrier, J, Schmitt Mechelke, T, Servidei, Serenella, Skardoutsou, A, Uldall, P, Van Der Knaap, M, Goglin, Kc, Tefft, Dl, Aubin, C, De Jager, P, Hafler, D, Warman, Ml, Servidei, Serenella (ORCID:0000-0001-8478-2799), Neilson, De, Adams, Md, Orr, Cmd, Schelling, Dk, Eiben, Rm, Kerr, D, Anderson, J, Bassuk, Ag, Bye, Am, Childs, A, Clarke, A, Crow, Yj, Di Rocco, M, Dohna Schwake, C, Dueckers, G, Fasano, Ae, Gika, Ad, Gionnis, D, Gorman, Mp, Grattan Smith, Pj, Hackenberg, A, Kuster, A, Lentschig, Mg, Lopez Laso, E, Marco, Ej, Mastroyianni, S, Perrier, J, Schmitt Mechelke, T, Servidei, Serenella, Skardoutsou, A, Uldall, P, Van Der Knaap, M, Goglin, Kc, Tefft, Dl, Aubin, C, De Jager, P, Hafler, D, Warman, Ml, and Servidei, Serenella (ORCID:0000-0001-8478-2799)
- Abstract
Acute necrotizing encephalopathy (ANE) is a rapidly progressive encephalopathy that can occur in otherwise healthy children after common viral infections such as influenza and parainfluenza. Most ANE is sporadic and nonrecurrent (isolated ANE). However, we identified a 7 Mb interval containing a susceptibility locus (ANE1) in a family segregating recurrent ANE as an incompletely penetrant, autosomal-dominant trait. We now report that all affected individuals and obligate carriers in this family are heterozygous for a missense mutation (c.1880C-->T, p.Thr585Met) in the gene encoding the nuclear pore protein Ran Binding Protein 2 (RANBP2). To determine whether this mutation is the susceptibility allele, we screened controls and other patients with ANE who are unrelated to the index family. Patients from 9 of 15 additional kindreds with familial or recurrent ANE had the identical mutation. It arose de novo in two families and independently in several other families. Two other patients with familial ANE had different RANBP2 missense mutations that altered conserved residues. None of the three RANBP2 missense mutations were found in 19 patients with isolated ANE or in unaffected controls. We conclude that missense mutations in RANBP2 are susceptibility alleles for familial and recurrent cases of ANE.
- Published
- 2009
13. 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
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- 2013
- Full Text
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14. A case of familial Labrune syndrome
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Berger, A, primary, Kutschke, G, additional, Crow, YJ, additional, and Reitter, B, additional
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- 2011
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15. Aicardi-Goutières syndrome presenting with haematemesis in infancy
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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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16. Mental retardation, keratoconus, febrile seizures and sinoatrial block: a previously undescribed autosomal recessive disorder
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Kirby, D, primary, Jackson, AP, additional, Karbani, G, additional, and Crow, YJ, additional
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- 2005
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17. 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]
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- 2010
- Full Text
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18. Aicardi-Goutières syndrome: description of a late onset case.
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D'Arrigo S, Riva D, Bulgheroni S, Chiapparini L, Lebon P, Rice G, Crow YJ, and Pantaleoni C
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- 2008
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19. Aicardi-Goutières syndrome: an important Mendelian mimic of congenital infection.
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Crow YJ, Livingston JH, Crow, Yanick J, and Livingston, John H
- Abstract
Aicardi-Goutières syndrome (AGS) is a rare, genetically determined encephalopathy whose importance from a clinical viewpoint is magnified because of the risk of misdiagnosis as the sequelae of congenital infection. Recent molecular advances have shown that AGS can be caused by mutations in any one of at least five genes (four of which have so far been identified), most commonly on a recessive basis but occasionally as a dominant trait. Additionally, a recent genotype-phenotype correlation has shown that two clinical presentations can be delineated; an early onset neonatal form highly reminiscent of congenital infection seen particularly with TREX1 mutations, and a later-onset presentation, sometimes occurring after several months of normal development and occasionally associated with remarkably preserved neurological function, most frequently due to RNASEH2B mutations. Evidence is emerging to show that the nucleases defective in AGS are involved in removing endogenous nucleic acid species produced during normal cellular processing, and that a failure of this removal results in inappropriate activation of the innate immune system. This hypothesis explains the phenotypic overlap of AGS with congenital infection and some aspects of systemic lupus erythematosus, where a similar interferon alpha-mediated innate immune response is triggered by viral and host nucleic acids respectively. [ABSTRACT FROM AUTHOR]
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- 2008
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20. Severe childhood SMA and axonal CMT due to anticodon binding domain mutations in the GARS gene.
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James PA, Cader MZ, Muntoni F, Childs AM, Crow YJ, Talbot K, James, P A, Cader, M Z, Muntoni, F, Childs, A-M, Crow, Y J, and Talbot, K
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- 2006
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21. Blue (or purple) toes: Chilblains or chilblain lupus-like lesions are a manifestation of Aicardi-Goutières syndrome and familial chilblain lupus.
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Prendiville JS and Crow YJ
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- 2009
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22. Elevated pterins in cerebral spinal fluid--biochemical marker of Aicardi-Goutières syndrome.
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Wassmer E, Singh J, Agrawal S, Santra S, and Crow YJ
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- 2009
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23. Clinical and molecular phenotype of Aicardi-Goutières syndrome.
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Crow YJ, Rice G, Patrick T, Parmar R, Flintoff K, Hayward B, Jackson A, Lebon P, Leitch A, and Taylor C
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- 2007
24. The neonatal form of Aicardi-Goutières syndrome masquerading as congenital infection.
- Author
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Jepps H, Seal S, Hattingh L, Crow YJ, Jepps, H, Seal, S, Hattingh, L, and Crow, Y J
- Abstract
Aicardi-Goutières syndrome (AGS) is a rare, genetically-determined encephalopathy whose importance from a neonatology perspective is magnified because of the risk of misdiagnosis as the sequelae of congenital infection. Molecular advances have shown that AGS can be caused by mutations in any one of at least five genes (four of which have been identified). A recent genotype-phenotype study has shown that a neonatal form of the disease, highly reminiscent of congenital infection, is seen particularly with TREX1 mutations. It seems likely that the enzymes defective in AGS are involved in digesting endogenous nucleic acids (DNA and RNA) produced during normal cell replication, and that a failure of this removal results in inappropriate triggering of the innate immune system. This hypothesis explains the remarkable phenotypic overlap of AGS with congenital infection, where a similar interferon alpha mediated innate immune response is triggered by viral, as opposed to self, nucleic acids. [ABSTRACT FROM AUTHOR]
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- 2008
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25. Mutations in MFSD8/CLN7 are a frequent cause of variant-late infantile neuronal ceroid lipofuscinosis
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Claudia Kitzmüller, Rosalba Carrozzo, Enrico Bertini, Marzia Bianchi, Yanick J. Crow, Roberta Biancheri, Mirella Filocamo, Renata Boldrini, Chiara Aiello, Filippo M. Santorelli, Alessandra Terracciano, Sara E. Mole, Antonietta Tavoni, Ruth Williams, Giancarlo Discepoli, Dianela Claps, Alessandra Tessa, Daniela Longo, Edwige Veneselli, Emilio Franzoni, Alessandro Simonati, Natalia Cannelli, Aiello C, Terracciano A, Simonati A, Discepoli G, Cannelli N, Claps D, Crow YJ, Bianchi M, Kitzmuller C, Longo D, Tavoni A, Franzoni E, Tessa A, Veneselli E, Boldrini R, Filocamo M, Williams RE, Bertini ES, Biancheri R, Carrozzo R, MoleSE, Santorelli FM. Hum Mutat. 2009 Jan 28, and 30(3):E530-E540. [Epub ahead of print]
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Male ,IDENTIFICATION GENE ,Adolescent ,Genetic counseling ,NEURONAL CEROID LIPOFUSCINOSIS ,DNA Mutational Analysis ,Molecular Sequence Data ,CHILDREN ,Biology ,medicine.disease_cause ,Frameshift mutation ,Gene product ,Gene Frequency ,Neuronal Ceroid-Lipofuscinoses ,Genetics ,medicine ,Missense mutation ,Humans ,Amino Acid Sequence ,Child ,Gene ,Genetics (clinical) ,Mutation ,Sequence Homology, Amino Acid ,Genetic heterogeneity ,MUTATIONS ,Membrane Transport Proteins ,medicine.disease ,Magnetic Resonance Imaging ,Pedigree ,Italy ,Child, Preschool ,Neuronal ceroid lipofuscinosis ,Female ,NEURODEGENERATIVE DISORDERS - Abstract
The neuronal ceroid lipofuscinoses (NCL) are a group of genetically heterogeneous neurodegenerative disorders. The recent identification of the MFSD8/CLN7 gene in a variant-late infantile form of NCL (v-LINCL) in affected children from Turkey prompted us to examine the relative frequency of variants in this gene in Italian patients with v-LINCL. We identified nine children harboring 11 different mutations in MFSD8/CLN7. Ten mutations were novel and included three nonsense (p.Arg35Stop, p.Glu381Stop, p.Arg482Stop), four missense (p.Met1Thr, p.Gly52Arg, p.Thr294Lys, p.Pro447Leu), two splice site mutations (c.863+3_4insT, c.863+1G>C), and a 17-bp deletion predicting a frameshift and premature protein truncation (c.627_643del17/p.Met209IlefsX3). The clinical phenotype, which was similar to that of the Turkish v-LINCL cases, was not influenced by type and location of the mutation nor the length of the predicted residual gene product. As well as identifying novel variants in MFSD8/CLN7, this study contributes to a better molecular characterization of Italian NCL cases, and will facilitate medical genetic counseling in such families. The existence of a subset of v-LINCL cases without mutations in any of the known NCL genes suggests further genetic heterogeneity. (c) 2009 Wiley-Liss, Inc.
- Published
- 2009
26. Mutations in CTC1, encoding conserved telomere maintenance component 1, cause Coats plus
- Author
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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
27. Mutations in the non-catalytic polyproline motif destabilize TREX1 and amplify cGAS-STING signaling.
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Shim A, Luan X, Zhou W, Crow YJ, and Maciejowski J
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- Humans, Amino Acid Motifs, HEK293 Cells, Lupus Erythematosus, Systemic genetics, Signal Transduction genetics, Autoimmune Diseases of the Nervous System genetics, Autoimmune Diseases of the Nervous System metabolism, Exodeoxyribonucleases genetics, Exodeoxyribonucleases metabolism, Membrane Proteins genetics, Membrane Proteins metabolism, Mutation, Nervous System Malformations genetics, Nucleotidyltransferases genetics, Nucleotidyltransferases metabolism, Phosphoproteins genetics, Phosphoproteins metabolism
- Abstract
The cGAS-STING pathway detects cytosolic DNA and activates a signaling cascade that results in a type I interferon (IFN) response. The endoplasmic reticulum (ER)-associated exonuclease TREX1 suppresses cGAS-STING by eliminating DNA from the cytosol. Mutations that compromise TREX1 function are linked to autoinflammatory disorders, including systemic lupus erythematosus (SLE) and Aicardi-Goutières syndrome (AGS). Despite key roles in regulating cGAS-STING and suppressing excessive inflammation, the impact of many disease-associated TREX1 mutations-particularly those outside of the core catalytic domains-remains poorly understood. Here, we characterize a recessive AGS-linked TREX1 P61Q mutation occurring within the poorly characterized polyproline helix (PPII) motif. In keeping with its position outside of the catalytic core or ER targeting motifs, neither the P61Q mutation, nor aggregate proline-to-alanine PPII mutation, disrupts TREX1 exonuclease activity, subcellular localization, or cGAS-STING regulation in overexpression systems. Introducing targeted mutations into the endogenous TREX1 locus revealed that PPII mutations destabilize the protein, resulting in impaired exonuclease activity and unrestrained cGAS-STING activation. Overall, these results demonstrate that TREX1 PPII mutations, including P61Q, impair proper immune regulation and lead to autoimmune disease through TREX1 destabilization., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
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- 2024
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28. 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
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- 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).)
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- 2024
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29. 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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30. The brain microvasculature is a primary mediator of interferon-α neurotoxicity in human cerebral interferonopathies.
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Viengkhou B, Hayashida E, McGlasson S, Emelianova K, Forbes D, Wiseman S, Wardlaw J, Verdillo R, Irani SR, Duffy D, Piehl F, Loo L, Pagenstecher A, Neely GG, Crow YJ, Campbell IL, Hunt DPJ, and Hofer MJ
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- Animals, Humans, Mice, Autoimmune Diseases of the Nervous System immunology, Endothelial Cells metabolism, Mice, Knockout, Male, Female, Signal Transduction, Mice, Inbred C57BL, Astrocytes metabolism, Disease Models, Animal, Interferon-alpha metabolism, Brain metabolism, Brain pathology, Receptor, Interferon alpha-beta metabolism, Receptor, Interferon alpha-beta genetics, Microvessels pathology, Nervous System Malformations genetics
- Abstract
Aicardi-Goutières syndrome (AGS) is an autoinflammatory disease characterized by aberrant interferon (IFN)-α production. The major cause of morbidity in AGS is brain disease, yet the primary source and target of neurotoxic IFN-α remain unclear. Here, we demonstrated that the brain was the primary source of neurotoxic IFN-α in AGS and confirmed the neurotoxicity of intracerebral IFN-α using astrocyte-driven Ifna1 misexpression in mice. Using single-cell RNA sequencing, we demonstrated that intracerebral IFN-α-activated receptor (IFNAR) signaling within cerebral endothelial cells caused a distinctive cerebral small vessel disease similar to that observed in individuals with AGS. Magnetic resonance imaging (MRI) and single-molecule ELISA revealed that central and not peripheral IFN-α was the primary determinant of microvascular disease in humans. Ablation of endothelial Ifnar1 in mice rescued microvascular disease, stopped the development of diffuse brain disease, and prolonged lifespan. These results identify the cerebral microvasculature as a primary mediator of IFN-α neurotoxicity in AGS, representing an accessible target for therapeutic intervention., Competing Interests: Declaration of interests I.L.C. and M.J.H. received funding from Ionis Pharmaceuticals for experiments in an unrelated study using the GIFN mice., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2024
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31. Human life within a narrow range: The lethal ups and downs of type I interferons.
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Crow YJ and Casanova JL
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- Humans, Animals, Virus Diseases immunology, Autoimmune Diseases immunology, Signal Transduction immunology, Interferon Type I immunology
- Abstract
The past 20 years have seen the definition of human monogenic disorders and their autoimmune phenocopies underlying either defective or enhanced type I interferon (IFN) activity. These disorders delineate the impact of type I IFNs in natural conditions and demonstrate that only a narrow window of type I IFN activity is beneficial. Insufficient type I IFN predisposes humans to life-threatening viral diseases (albeit unexpectedly few) with a central role in immunity to respiratory and cerebral viral infection. Excessive type I IFN, perhaps counterintuitively, appears to underlie a greater number of autoinflammatory and/or autoimmune conditions known as type I interferonopathies, whose study has revealed multiple molecular programs involved in the induction of type I IFN signaling. These observations suggest that the manipulation of type I IFN activity to within a physiological range may be clinically relevant for the prevention and treatment of viral and inflammatory diseases.
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- 2024
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32. Biallelic NAA60 variants with impaired n-terminal acetylation capacity cause autosomal recessive primary familial brain calcifications.
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Chelban V, Aksnes H, Maroofian R, LaMonica LC, Seabra L, Siggervåg A, Devic P, Shamseldin HE, Vandrovcova J, Murphy D, Richard AC, Quenez O, Bonnevalle A, Zanetti MN, Kaiyrzhanov R, Salpietro V, Efthymiou S, Schottlaender LV, Morsy H, Scardamaglia A, Tariq A, Pagnamenta AT, Pennavaria A, Krogstad LS, Bekkelund ÅK, Caiella A, Glomnes N, Brønstad KM, Tury S, Moreno De Luca A, Boland-Auge A, Olaso R, Deleuze JF, Anheim M, Cretin B, Vona B, Alajlan F, Abdulwahab F, Battini JL, İpek R, Bauer P, Zifarelli G, Gungor S, Kurul SH, Lochmuller H, Da'as SI, Fakhro KA, Gómez-Pascual A, Botía JA, Wood NW, Horvath R, Ernst AM, Rothman JE, McEntagart M, Crow YJ, Alkuraya FS, Nicolas G, Arnesen T, and Houlden H
- Subjects
- Humans, Acetylation, Brain diagnostic imaging, Brain metabolism, Inheritance Patterns, Mutation, Phosphates metabolism, Sodium-Phosphate Cotransporter Proteins, Type III metabolism, Brain Diseases genetics
- Abstract
Primary familial brain calcification (PFBC) is characterized by calcium deposition in the brain, causing progressive movement disorders, psychiatric symptoms, and cognitive decline. PFBC is a heterogeneous disorder currently linked to variants in six different genes, but most patients remain genetically undiagnosed. Here, we identify biallelic NAA60 variants in ten individuals from seven families with autosomal recessive PFBC. The NAA60 variants lead to loss-of-function with lack of protein N-terminal (Nt)-acetylation activity. We show that the phosphate importer SLC20A2 is a substrate of NAA60 in vitro. In cells, loss of NAA60 caused reduced surface levels of SLC20A2 and a reduction in extracellular phosphate uptake. This study establishes NAA60 as a causal gene for PFBC, provides a possible biochemical explanation of its disease-causing mechanisms and underscores NAA60-mediated Nt-acetylation of transmembrane proteins as a fundamental process for healthy neurobiological functioning., (© 2024. The Author(s).)
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- 2024
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33. NOTCH1-Related Leukoencephalopathy: A Novel Variant and Literature Review.
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Della Vecchia S, Tessa A, Pasquariello R, Seabra L, Crow YJ, and Battini R
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- Male, Adolescent, Humans, Brain, Mutation, Magnetic Resonance Imaging, Receptor, Notch1 genetics, Leukoencephalopathies genetics, Nervous System Malformations genetics, Cysts
- Abstract
NOTCH1 -related leukoencephalopathy is a new diagnostic entity linked to heterozygous gain-of-function variants in NOTCH1 that neuroradiologically show some overlap with the inflammatory microangiopathy Aicardi-Goutières syndrome (AGS). To report a 16-year-old boy harbouring a novel NOTCH1 mutation who presented neuroradiological features suggestive of enhanced type I interferon signalling. We describe five years of follow-up and review the current literature on NOTCH1 -related leukoencephalopathy. Clinical evaluation, standardised scales (SPRS, SARA, CBCL, CDI-2:P, WISCH-IV and VABS-2) and neuroradiological studies were performed, as well as blood DNA analysis. For the literature review, a search was performed on Pubmed, Scopus and Web of Science up to December 2023 using the following text word search strategy: ( NOTCH1 ) AND (leukoencephalopathy). Our patient presents clinical features consistent with other reported cases with NOTCH1 mutations but is among the minority of patients with an onset after infancy. During the five-year follow-up, we observed an increase in the severity of spasticity and ataxia. However, at the age of 16 years, our proband is still ambulatory. As for other reported patients, he manifests psychiatric features ranging from hyperactivity during childhood to anxiety and depression during adolescence. The neuroradiological picture remained essentially stable over five years. In addition to the typical findings of leukoencephalopathy with cysts and calcifications already described, we report the presence of T2-hyperintensity and T1-hypotensity of the transverse pontine fibres, enhancement in the periventricular white matter after gadolinium administration and decreased NAA and Cho peaks in the periventricular white matter on MRS. We identified a novel heterozygous variant in NOTCH1 (c.4788_4799dup), a frame insertion located in extracellular negative regulatory region (NRR)-domain as in previously published cases. Blood interferon signalling was not elevated compared to controls. This case provides further data on a new diagnostic entity, i.e., NOTCH1-related leukoencephalopathy. By describing a standardised five-year follow-up in one case and reviewing the other patients described to date, we outline recommendations relating to monitoring in this illness, emphasising the importance of psychiatric and gastroenterological surveillance alongside neurological and neuropsychological management. Studies are needed to better understand the factors influencing disease onset and severity, which are heterogeneous.
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- 2024
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34. 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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35. Phenotypes associated with genetic determinants of type I interferon regulation in the UK Biobank: a protocol.
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Rioux B, Chong M, Walker R, McGlasson S, Rannikmäe K, McCartney D, McCabe J, Brown R, Crow YJ, Hunt D, and Whiteley W
- Abstract
Background: Type I interferons are cytokines involved in innate immunity against viruses. Genetic disorders of type I interferon regulation are associated with a range of autoimmune and cerebrovascular phenotypes. Carriers of pathogenic variants involved in genetic disorders of type I interferons are generally considered asymptomatic. Preliminary data suggests, however, that genetically determined dysregulation of type I interferon responses is associated with autoimmunity, and may also be relevant to sporadic cerebrovascular disease and dementia. We aim to determine whether functional variants in genes involved in type I interferon regulation and signalling are associated with the risk of autoimmunity, stroke, and dementia in a population cohort., Methods: We will perform a hypothesis-driven candidate pathway association study of type I interferon-related genes using rare variants in the UK Biobank (UKB). We will manually curate type I interferon regulation and signalling genes from a literature review and Gene Ontology, followed by clinical and functional filtering. Variants of interest will be included based on pre-defined clinical relevance and functional annotations (using LOFTEE, M-CAP and a minor allele frequency <0.1%). The association of variants with 15 clinical and three neuroradiological phenotypes will be assessed with a rare variant genetic risk score and gene-level tests, using a Bonferroni-corrected p-value threshold from the number of genetic units and phenotypes tested. We will explore the association of significant genetic units with 196 additional health-related outcomes to help interpret their relevance and explore the clinical spectrum of genetic perturbations of type I interferon., Ethics and Dissemination: The UKB has received ethical approval from the North West Multicentre Research Ethics Committee, and all participants provided written informed consent at recruitment. This research will be conducted using the UKB Resource under application number 93160. We expect to disseminate our results in a peer-reviewed journal and at an international cardiovascular conference., Competing Interests: No competing interests were disclosed., (Copyright: © 2023 Rioux B et al.)
- Published
- 2023
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36. ARF1 prevents aberrant type I interferon induction by regulating STING activation and recycling.
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Hirschenberger M, Lepelley A, Rupp U, Klute S, Hunszinger V, Koepke L, Merold V, Didry-Barca B, Wondany F, Bergner T, Moreau T, Rodero MP, Rösler R, Wiese S, Volpi S, Gattorno M, Papa R, Lynch SA, Haug MG, Houge G, Wigby KM, Sprague J, Lenberg J, Read C, Walther P, Michaelis J, Kirchhoff F, de Oliveira Mann CC, Crow YJ, and Sparrer KMJ
- Subjects
- Humans, ADP-Ribosylation Factor 1 genetics, ADP-Ribosylation Factor 1 metabolism, Membrane Proteins metabolism, Nucleotidyltransferases genetics, Nucleotidyltransferases metabolism, Signal Transduction, Interferon Type I metabolism
- Abstract
Type I interferon (IFN) signalling is tightly controlled. Upon recognition of DNA by cyclic GMP-AMP synthase (cGAS), stimulator of interferon genes (STING) translocates along the endoplasmic reticulum (ER)-Golgi axis to induce IFN signalling. Termination is achieved through autophagic degradation or recycling of STING by retrograde Golgi-to-ER transport. Here, we identify the GTPase ADP-ribosylation factor 1 (ARF1) as a crucial negative regulator of cGAS-STING signalling. Heterozygous ARF1 missense mutations cause a previously unrecognized type I interferonopathy associated with enhanced IFN-stimulated gene expression. Disease-associated, GTPase-defective ARF1 increases cGAS-STING dependent type I IFN signalling in cell lines and primary patient cells. Mechanistically, mutated ARF1 perturbs mitochondrial morphology, causing cGAS activation by aberrant mitochondrial DNA release, and leads to accumulation of active STING at the Golgi/ERGIC due to defective retrograde transport. Our data show an unexpected dual role of ARF1 in maintaining cGAS-STING homeostasis, through promotion of mitochondrial integrity and STING recycling., (© 2023. Springer Nature Limited.)
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- 2023
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37. Case report: Clinical and neuroradiological longitudinal follow-up in Leukoencephalopathy with Calcifications and Cysts during treatment with bevacizumab.
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Scaffei E, Buchignani B, Pasquariello R, Cristofani P, Canapicchi R, Biagi L, Giordano F, De Marco E, Crow YJ, and Battini R
- Abstract
Leukoencephalopathy with Calcifications and Cysts (LCC) is a rare genetic microangiopathy exclusively affecting the central nervous system caused by biallelic mutations in SNORD118 . Brain magnetic resonance imaging (MRI) is often diagnostic due to the highly characteristic triad of leukoencephalopathy, intracranial calcifications, and brain cysts. Age at onset, presentation and disease evolution can all vary, ranging from pauci-symptomatic disease to rapid evolution of signs with loss of motor and cognitive abilities. No specific therapies for LCC are currently licensed. According to the literature, bevacizumab might represent an effective modality to improve the clinical and MRI features of the disease. However, uncertainty remains as to the true efficacy of this approach, when to begin therapy, appropriate dosing, and the consequences of drug withdrawal. According to CARE guidelines, we describe the long-term clinical and neuro-radiological follow-up of a 10-year-old child with LCC. We report disease evolution following repeated cycles of treatment with bevacizumab. Our case report suggests that repeated cycles of bevacizumab might effectively modify disease progression, possibly indicating a time-dependent effect., 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 Scaffei, Buchignani, Pasquariello, Cristofani, Canapicchi, Biagi, Giordano, De Marco, Crow and Battini.)
- Published
- 2023
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38. 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).)
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- 2023
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39. STING-Associated Vasculopathy with Onset in infancy (SAVI) Presenting as Massive Intra Alveolar Hemorrhage.
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Ladoux C, Pasquet M, Crow YJ, Frémond ML, and Roditis L
- Subjects
- Humans, Infant, Hemorrhage diagnosis, Hemorrhage etiology, Inflammation, Vascular Diseases
- Published
- 2023
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40. Clinical Non-penetrance Associated with Biallelic Mutations in the RNase H2 Complex.
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Crow YJ
- Subjects
- Humans, Mutation genetics, Ribonucleases genetics, Autoimmune Diseases of the Nervous System genetics
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- 2023
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41. 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
- Subjects
- 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).)
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- 2023
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42. VEXAS syndrome: Expanding the clinical and molecular spectrum.
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Robert M, Berleur M, Gaudemer A, Crow YJ, Frémond ML, and Sacré K
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- Humans, Mutation, Myelodysplastic Syndromes genetics, Skin Diseases, Genetic
- Published
- 2023
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43. 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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44. Molecular characterization of an intronic RNASEH2B variant in a patient with Aicardi-Goutières syndrome.
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Leung ML, Woodhull W, Uggenti C, Schord S, Mato RP, Rodriguez DP, Ream M, Crow YJ, and Mori M
- Subjects
- Humans, Mutation, Exome, Autoimmune Diseases of the Nervous System genetics, Nervous System Malformations genetics
- Abstract
Aicardi-Goutières syndrome (AGS) is a progressive multisystem disorder including encephalopathy with significant impacts on intellectual and physical abilities. An early diagnosis is becoming ever more crucial, as targeted therapies are emerging. A deep understanding of the molecular heterogeneity of AGS can help guide the early diagnosis and clinical management of patients, and inform recurrence risks. Here, we detail the diagnostic odyssey of a patient with an early presentation of AGS. Exome and genome sequencing detected an intronic RNASEH2B variant missed in a conventional leukodystrophy NGS gene panel. RNA studies demonstrated that a c.322-17 A > G variant affected splicing and caused 16-nucleotide intronic retention in the RNASEH2B transcript, introducing an out-of-frame early termination codon. RNASEH2B expression in the patient's blood was reduced when compared to controls. Our study highlights the pathogenicity of this intronic variant and the importance of its inclusion in variant assessment., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)
- Published
- 2023
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45. The type I interferonopathies: 10 years on.
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Crow YJ and Stetson DB
- Subjects
- Humans, Immunity, Innate, Pandemics, COVID-19, Interferon Type I genetics, Nucleic Acids
- Abstract
As brutally demonstrated by the COVID-19 pandemic, an effective immune system is essential for survival. Developed over evolutionary time, viral nucleic acid detection is a central pillar in the defensive armamentarium used to combat foreign microbial invasion. To ensure cellular homeostasis, such a strategy necessitates the efficient discrimination of pathogen-derived DNA and RNA from that of the host. In 2011, it was suggested that an upregulation of type I interferon signalling might serve as a defining feature of a novel set of Mendelian inborn errors of immunity, where antiviral sensors are triggered by host nucleic acids due to a failure of self versus non-self discrimination. These rare disorders have played a surprisingly significant role in informing our understanding of innate immunity and the relevance of type I interferon signalling for human health and disease. Here we consider what we have learned in this time, and how the field may develop in the future., (© 2021. Springer Nature Limited.)
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- 2022
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46. 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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47. Delineating the epilepsy phenotype of NRROS-related microgliopathy: A case report and literature review.
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Madaan P, Kaushal Y, Srivastava P, Crow YJ, Livingston JH, Ahuja C, and Sankhyan N
- Subjects
- Humans, Neuroimaging, Phenotype, Seizures complications, Calcinosis complications, Epilepsy diagnosis, Neurodegenerative Diseases complications, Spasms, Infantile diagnosis
- Abstract
Background: Negative regulator of reactive oxygen species (NRROS) related microgliopathy, a rare and recently recognized neurodegenerative condition, is caused by pathogenic variants in the NRROS gene, which plays a major role in the regulation of transforming growth factor-beta 1., Methods: We report a child presenting with infantile spasms syndrome (ISS) with subsequent progressive neurodegeneration who was identified to harbour a novel likely pathogenic NRROS variant (c.1359del; p.Ser454Alafs*11). The previously published reports of patients with this disorder were also reviewed systematically., Results: Including our index patient, 11 children (6 girls) were identified in total. Early development was normal in seven of these eleven children. All had a history of drug-resistant epilepsy, with 3 having epileptic spasms. The median age at seizure onset and developmental regression was 12 months, and the median age at death was 36 months. Intracranial calcifications were described in eight of eleven children. Neuroimaging revealed progressive cerebral atrophy and white matter loss in all children. The most common reported genetic variation was c.1981delC; (p.Leu661Serfs*97) observed in two families (likely due to a founder effect)., Conclusions: Pathogenic variants in NRROS should be suspected in children with neuro-regression and drug-resistant epilepsy including ISS with onset in the first two years of life. Punctate or serpiginous calcifications at the grey-white matter junction and acquired microcephaly are further clues towards the diagnosis., (Copyright © 2022. Published by Elsevier Ltd.)
- Published
- 2022
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48. 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).)
- Published
- 2022
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49. Type I interferon-related kidney disorders.
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Lodi L, Mastrolia MV, Bello F, Rossi GM, Angelotti ML, Crow YJ, Romagnani P, and Vaglio A
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- Antiviral Agents, Humans, Kidney metabolism, Kidney Glomerulus metabolism, Interferon Type I adverse effects, Interferon Type I metabolism, Kidney Diseases chemically induced, Kidney Diseases genetics, Lupus Erythematosus, Systemic drug therapy, Lupus Erythematosus, Systemic genetics
- Abstract
Type I interferon (IFN-I) mediates tissue damage in a wide range of kidney disorders, directly affecting the biology and function of several renal cell types including podocytes, mesangial, endothelial, and parietal epithelial cells. Enhanced IFN-I signaling is observed in the context of viral infections, autoimmunity (e.g., systemic lupus erythematosus), and type 1 interferonopathies, rare monogenic disorders characterized by constitutive activation of the IFN-I pathway. All these IFN-I-related disorders can cause renal dysfunction and share pathogenic and histopathological features. Collapsing glomerulopathy, a histopathological lesion characterized by podocyte loss, collapse of the vascular tuft, and parietal epithelial cell proliferation, is commonly associated with viral infections, has been described in type 1 interferonopathies such as Aicardi-Goutières syndrome and stimulator of IFN genes-associated vasculopathy with onset in infancy, and can also be induced by recombinant IFN therapy. In all these conditions, podocytes and parietal epithelial cells seem to be the primary target of IFN-I-mediated damage. Additionally, immune-mediated glomerular injury is common to viral infections, systemic lupus erythematosus, and type 1 interferonopathies such as coatomer subunit-α syndrome (COPA) and DNASE1L3 deficiency, diseases in which IFN-I apparently promotes immune-mediated kidney injury. Finally, kidney pathology primarily characterized by vascular lesions (e.g., thrombotic microangiopathy and vasculitis) is a hallmark of type 1 interferonopathy adenosine deaminase 2 deficiency as well as of systemic lupus erythematosus, viral infections, and IFN therapy. Defining the nosology, pathogenic mechanisms, and histopathological patterns of IFN-I-related kidney disorders has diagnostic and therapeutic implications, especially considering the likely near-term availability of novel drugs targeting the IFN-I pathway., (Copyright © 2022 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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50. Global mapping of RNA homodimers in living cells.
- Author
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Gabryelska MM, Badrock AP, Lau JY, O'Keefe RT, Crow YJ, and Kudla G
- Subjects
- Animals, Base Sequence, RNA, Small Nucleolar genetics, RNA, Viral genetics, SARS-CoV-2 genetics, Zebrafish genetics, COVID-19, Zika Virus genetics, Zika Virus Infection genetics
- Abstract
RNA homodimerization is important for various physiological processes, including the assembly of membraneless organelles, RNA subcellular localization, and packaging of viral genomes. However, understanding RNA dimerization has been hampered by the lack of systematic in vivo detection methods. Here, we show that CLASH, PARIS, and other RNA proximity ligation methods detect RNA homodimers transcriptome-wide as "overlapping" chimeric reads that contain more than one copy of the same sequence. Analyzing published proximity ligation data sets, we show that RNA:RNA homodimers mediated by direct base-pairing are rare across the human transcriptome, but highly enriched in specific transcripts, including U8 snoRNA, U2 snRNA, and a subset of tRNAs. Mutations in the homodimerization domain of U8 snoRNA impede dimerization in vitro and disrupt zebrafish development in vivo, suggesting an evolutionarily conserved role of this domain. Analysis of virus-infected cells reveals homodimerization of SARS-CoV-2 and Zika genomes, mediated by specific palindromic sequences located within protein-coding regions of N gene in SARS-CoV-2 and NS2A gene in Zika. We speculate that regions of viral genomes involved in homodimerization may constitute effective targets for antiviral therapies., (© 2022 Gabryelska et al.; Published by Cold Spring Harbor Laboratory Press.)
- Published
- 2022
- Full Text
- View/download PDF
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