RESUMO
PURPOSE: Increased type I interferon is considered relevant to the pathology of a number of monogenic and complex disorders spanning pediatric rheumatology, neurology, and dermatology. However, no test exists in routine clinical practice to identify enhanced interferon signaling, thus limiting the ability to diagnose and monitor treatment of these diseases. Here, we set out to investigate the use of an assay measuring the expression of a panel of interferon-stimulated genes (ISGs) in children affected by a range of inflammatory diseases. DESIGN, SETTING, AND PARTICIPANTS: A cohort study was conducted between 2011 and 2016 at the University of Manchester, UK, and the Institut Imagine, Paris, France. RNA PAXgene blood samples and clinical data were collected from controls and symptomatic patients with a genetically confirmed or clinically well-defined inflammatory phenotype. The expression of six ISGs was measured by quantitative polymerase chain reaction, and the median fold change was used to calculate an interferon score (IS) for each subject compared to a previously derived panel of 29 controls (where +2 SD of the control data, an IS of >2.466, is considered as abnormal). Results were correlated with genetic and clinical data. RESULTS: Nine hundred ninety-two samples were analyzed from 630 individuals comprising symptomatic patients across 24 inflammatory genotypes/phenotypes, unaffected heterozygous carriers, and controls. A consistent upregulation of ISG expression was seen in 13 monogenic conditions (455 samples, 265 patients; median IS 10.73, interquartile range (IQR) 5.90-18.41), juvenile systemic lupus erythematosus (78 samples, 55 patients; median IS 10.60, IQR 3.99-17.27), and juvenile dermatomyositis (101 samples, 59 patients; median IS 9.02, IQR 2.51-21.73) compared to controls (78 samples, 65 subjects; median IS 0.688, IQR 0.427-1.196), heterozygous mutation carriers (89 samples, 76 subjects; median IS 0.862, IQR 0.493-1.942), and individuals with non-molecularly defined autoinflammation (89 samples, 69 patients; median IS 1.07, IQR 0.491-3.74). CONCLUSIONS AND RELEVANCE: An assessment of six ISGs can be used to define a spectrum of inflammatory diseases related to enhanced type I interferon signaling. If future studies demonstrate that the IS is a reactive biomarker, this measure may prove useful both in the diagnosis and the assessment of treatment efficacy.
Assuntos
Inflamação/etiologia , Inflamação/metabolismo , Interferon Tipo I/metabolismo , Transdução de Sinais , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Estudos de Associação Genética , Genótipo , Humanos , Lactente , Recém-Nascido , Inflamação/diagnóstico , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/metabolismo , Masculino , Pessoa de Meia-Idade , Fenótipo , Adulto JovemRESUMO
Although ribosomes are ubiquitous and essential for life, recent data indicate that monogenic causes of ribosomal dysfunction can confer a remarkable degree of specificity in terms of human disease phenotype. Box C/D small nucleolar RNAs (snoRNAs) are evolutionarily conserved non-protein-coding RNAs involved in ribosome biogenesis. Here we show that biallelic mutations in the gene SNORD118, encoding the box C/D snoRNA U8, cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts (LCC), presenting at any age from early childhood to late adulthood. These mutations affect U8 expression, processing and protein binding and thus implicate U8 as essential in cerebral vascular homeostasis.
Assuntos
Doenças de Pequenos Vasos Cerebrais/genética , Leucoencefalopatias/genética , Mutação , RNA Nucleolar Pequeno/genética , Adolescente , Adulto , Calcinose/genética , Calcinose/patologia , Linhagem Celular , Doenças de Pequenos Vasos Cerebrais/patologia , Criança , Pré-Escolar , Cromossomos Humanos Par 17 , Estudos de Coortes , Cistos/genética , Cistos/patologia , Exoma , Feminino , Ligação Genética , Genoma Humano , Humanos , Lactente , Leucoencefalopatias/patologia , Masculino , Pessoa de Meia-Idade , Análise de Sequência de DNA , Adulto JovemRESUMO
IMPORTANCE: The type I interferonopathies comprise a recently recognized group of mendelian diseases characterized by an upregulation of type I interferon signaling. These monogenic phenotypes include classic Aicardi-Goutières syndrome and syndromic forms of systemic lupus erythematosus, including familial chilblain lupus and spondyloenchondrodysplasia. Dermatologic features provide a major diagnostic clue to this disease grouping, as exemplified by the recently described stimulator of interferon genes-associated vasculopathy with onset in infancy (SAVI) caused by gain-of-function mutations in TMEM173. OBSERVATIONS: We describe a male child who, from the age of 2 months, had significant cutaneous disease that manifested as red violaceous plaques of the cheeks, nose, ears, fingers, and toes that progressed to gangrenous necrosis. In addition to his severe cutaneous vasculopathy, he experienced recurrent fevers, interstitial lung disease, and failure to thrive. His clinical syndrome was refractory to multiple immunosuppressive therapies. Evidence of marked upregulation of type I interferon signaling was observed in peripheral blood, and genetic testing identified a de novo germline mutation in TMEM173, confirming a diagnosis of SAVI 7 years after the onset of his disease. CONCLUSIONS AND RELEVANCE: This observational report describes a new case of SAVI, a recently defined monogenic inflammatory phenotype, that exemplifies an emerging group of disorders related to primary upregulation of type I interferon signaling.
Assuntos
Granulomatose com Poliangiite/diagnóstico , Interferon Tipo I/genética , Proteínas de Membrana/genética , Dermatopatias Vasculares/diagnóstico , Humanos , Lactente , Masculino , Mutação , Fenótipo , Dermatopatias Vasculares/genética , Dermatopatias Vasculares/patologia , Regulação para CimaRESUMO
Aicardi-Goutières syndrome is an inflammatory disease occurring due to mutations in any of TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR or IFIH1. We report on 374 patients from 299 families with mutations in these seven genes. Most patients conformed to one of two fairly stereotyped clinical profiles; either exhibiting an in utero disease-onset (74 patients; 22.8% of all patients where data were available), or a post-natal presentation, usually within the first year of life (223 patients; 68.6%), characterized by a sub-acute encephalopathy and a loss of previously acquired skills. Other clinically distinct phenotypes were also observed; particularly, bilateral striatal necrosis (13 patients; 3.6%) and non-syndromic spastic paraparesis (12 patients; 3.4%). We recorded 69 deaths (19.3% of patients with follow-up data). Of 285 patients for whom data were available, 210 (73.7%) were profoundly disabled, with no useful motor, speech and intellectual function. Chilblains, glaucoma, hypothyroidism, cardiomyopathy, intracerebral vasculitis, peripheral neuropathy, bowel inflammation and systemic lupus erythematosus were seen frequently enough to be confirmed as real associations with the Aicardi-Goutieres syndrome phenotype. We observed a robust relationship between mutations in all seven genes with increased type I interferon activity in cerebrospinal fluid and serum, and the increased expression of interferon-stimulated gene transcripts in peripheral blood. We recorded a positive correlation between the level of cerebrospinal fluid interferon activity assayed within one year of disease presentation and the degree of subsequent disability. Interferon-stimulated gene transcripts remained high in most patients, indicating an ongoing disease process. On the basis of substantial morbidity and mortality, our data highlight the urgent need to define coherent treatment strategies for the phenotypes associated with mutations in the Aicardi-Goutières syndrome-related genes. Our findings also make it clear that a window of therapeutic opportunity exists relevant to the majority of affected patients and indicate that the assessment of type I interferon activity might serve as a useful biomarker in future clinical trials.
Assuntos
Adenosina Desaminase/genética , Doenças Autoimunes do Sistema Nervoso/diagnóstico , Doenças Autoimunes do Sistema Nervoso/genética , RNA Helicases DEAD-box/genética , Exodesoxirribonucleases/genética , Proteínas Monoméricas de Ligação ao GTP/genética , Mutação , Malformações do Sistema Nervoso/diagnóstico , Malformações do Sistema Nervoso/genética , Fenótipo , Fosfoproteínas/genética , Ribonuclease H/genética , Estudos de Associação Genética , Genótipo , Humanos , Helicase IFIH1 Induzida por Interferon , Interferons/sangue , Interferons/líquido cefalorraquidiano , Pterinas/líquido cefalorraquidiano , Proteína 1 com Domínio SAM e Domínio HDRESUMO
BACKGROUND: A reduction of ADA2 activity due to autosomal recessive loss of function mutations in CECR1 results in a newly described vasculopathic phenotype reminiscent of polyarteritis nodosa, with manifestations ranging from fatal systemic vasculitis with multiple strokes in children to limited cutaneous disease in middle-aged individuals. Evidence indicates that ADA2 is essential for the endothelial integrity of small vessels. However, CECR1 is not expressed, nor is the ADA2 protein detectable, in cultured human endothelial cells, thus implicating additional cell types or circulating factors in disease pathogenesis. METHODS: Considering the phenotypic overlap of ADA2 deficiency with the type I interferonopathy Aicardi-Goutières syndrome due to mutations in SAMHD1, we looked for the presence of an interferon signature in the peripheral blood of two newly ascertained ADA2-deficient patients. RESULTS: We identified biallelic CECR1 mutations in two patients consistent with ADA2 deficiency. Both patients demonstrated an upregulation of interferon stimulated gene transcripts in peripheral blood. More strikingly however, genome-wide analysis revealed a marked overexpression of neutrophil-derived genes, suggesting that the vasculitis seen in ADA2 deficiency may be an indirect effect resulting from chronic and marked activity of neutrophils. CONCLUSIONS: We hypothesise that ADA2 may act as a regulator of neutrophil activation, and that a reduction of ADA2 activity results in significant endothelial damage via a neutrophil-driven process.
Assuntos
Adenosina Desaminase/deficiência , Agamaglobulinemia/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Mutação/genética , Ativação de Neutrófilo/genética , Neutrófilos/patologia , Imunodeficiência Combinada Severa/genética , Adenosina Desaminase/sangue , Adenosina Desaminase/genética , Agamaglobulinemia/sangue , Alelos , Criança , Estudo de Associação Genômica Ampla , Humanos , Interferons/sangue , Masculino , Proteínas Monoméricas de Ligação ao GTP/genética , Proteína 1 com Domínio SAM e Domínio HD , Imunodeficiência Combinada Severa/sangue , Vasculite/sangue , Vasculite/genética , Adulto JovemRESUMO
BACKGROUND: Beta-propeller protein-associated neurodegeneration is a newly described X-linked dominant condition due to heterozygous mutations in WDR45. The condition is associated with characteristic changes on brain magnetic resonance imaging. Previous literature relating to this disorder has not specifically referred to intracranial calcification. METHODS: A female patient presented with significant developmental delay in early childhood and subsequently demonstrated neurodegeneration with progressive dystonia and dementia in her third decade. Brain magnetic resonance imaging revealed low signal in the substantia nigra and both globus pallidi on T2-weighted imaging, with no eye-of-the-tiger sign. Computed tomography revealed bilateral dense calcification of the globus pallidus. We performed Sanger sequencing of the WDR45 gene in the patient and her parents. RESULTS: We identified a heterozygous c.488del C p.Pro163Argfs*34 variant in exon 8 of WDR45. Neither parent carried the same mutation, indicating that the molecular change had occurred de novo. CONCLUSIONS: Although the characteristic features of beta-propeller protein-associated neurodegeneration were present in our patient, the observation of basal ganglia calcification was considered atypical. Previous descriptions of basal ganglia calcification in individuals with neuronal brain iron accumulation led us to review the frequency of calcification in these disorders.
Assuntos
Gânglios da Base/patologia , Calcinose/patologia , Distúrbios do Metabolismo do Ferro/patologia , Distrofias Neuroaxonais/patologia , Adulto , Proteínas de Transporte/genética , Feminino , Humanos , Distúrbios do Metabolismo do Ferro/classificação , Distúrbios do Metabolismo do Ferro/genética , Distrofias Neuroaxonais/classificação , Distrofias Neuroaxonais/genéticaRESUMO
Identification of de novo minisatellite mutations in the offspring of parents exposed to mutagenic agents offers a potentially sensitive measure of germ line genetic events induced by ionizing radiation and genotoxic chemicals. Germ line minisatellite mutations (GMM) are usually detected by hybridizing Southern blots of unamplified size-fractionated genomic DNA with minisatellite probes. However, this consumes a relatively large amount of DNA, requires several steps and may lack sensitivity. We have developed a polymerase chain reaction (PCR)-based GMM assay, which we applied to the hypermutable minisatellite, CEB1. Here, we compare the sensitivity and specificity of this assay with the conventional Southern hybridization method using DNA from 10 spouse pairs, one parent of each pair being a survivor of cancer in childhood, and their 20 offspring. We report that both methods have similar specificity but that the PCR method uses 250 times less DNA, has fewer steps and is better at detecting GMM with single repeats provided that specific guidelines for allele sizing are followed. The PCR GMM method is easier to apply to families where the amount of offspring DNA sample is limited.