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1.
Nat Med ; 25(12): 1873-1884, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31806906

RESUMO

Herpes simplex virus-1 (HSV-1) encephalitis (HSE) is typically sporadic. Inborn errors of TLR3- and DBR1-mediated central nervous system cell-intrinsic immunity can account for forebrain and brainstem HSE, respectively. We report five unrelated patients with forebrain HSE, each heterozygous for one of four rare variants of SNORA31, encoding a small nucleolar RNA of the H/ACA class that are predicted to direct the isomerization of uridine residues to pseudouridine in small nuclear RNA and ribosomal RNA. We show that CRISPR/Cas9-introduced bi- and monoallelic SNORA31 deletions render human pluripotent stem cell (hPSC)-derived cortical neurons susceptible to HSV-1. Accordingly, SNORA31-mutated patient hPSC-derived cortical neurons are susceptible to HSV-1, like those from TLR3- or STAT1-deficient patients. Exogenous interferon (IFN)-ß renders SNORA31- and TLR3- but not STAT1-mutated neurons resistant to HSV-1. Finally, transcriptome analysis of SNORA31-mutated neurons revealed normal responses to TLR3 and IFN-α/ß stimulation but abnormal responses to HSV-1. Human SNORA31 thus controls central nervous system neuron-intrinsic immunity to HSV-1 by a distinctive mechanism.


Assuntos
Encefalite por Herpes Simples/genética , Herpesvirus Humano 1/genética , Neurônios/imunologia , RNA Nucleolar Pequeno/genética , Adulto , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/virologia , Pré-Escolar , Encefalite por Herpes Simples/imunologia , Encefalite por Herpes Simples/patologia , Encefalite por Herpes Simples/virologia , Feminino , Predisposição Genética para Doença , Herpesvirus Humano 1/imunologia , Herpesvirus Humano 1/patogenicidade , Humanos , Imunidade/genética , Lactente , Masculino , Metagenoma/genética , Metagenoma/imunologia , Pessoa de Meia-Idade , Neurônios/virologia , RNA Nucleolar Pequeno/imunologia
2.
Front Genet ; 10: 1024, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31749832

RESUMO

Despite the astonishing progress in treating chronic hepatitis C virus (HCV) infection with direct-acting antiviral agents, liver fibrosis remains a major health concern in HCV infected patients, in particular due to the treatment cost and insufficient HCV screening in many countries. Only a fraction of patients with chronic HCV infection develop liver fibrosis. While there is evidence that host genetic factors are involved in the development of liver fibrosis, the common variants identified so far, in particular by genome-wide association studies, were found to have limited effects. Here, we conducted an exome association study in 88 highly selected HCV-infected patients with and without fibrosis. A strategy focusing on TGF-ß pathway genes revealed an enrichment in rare variants of the endoglin gene (ENG) in fibrosis patients. Replication studies in additional cohorts (617 patients) identified one specific ENG variant, Thr5Met, with an overall odds ratio for fibrosis development in carriers of 3.04 (1.39-6.69). Our results suggest that endoglin, a key player in TGF-ß signaling, is involved in HCV-related liver fibrogenesis.

3.
Plant Biotechnol J ; 17(7): 1418-1430, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30582651

RESUMO

Coffee species such as Coffea canephora P. (Robusta) and C. arabica L. (Arabica) are important cash crops in tropical regions around the world. C. arabica is an allotetraploid (2n = 4x = 44) originating from a hybridization event of the two diploid species C. canephora and C. eugenioides (2n = 2x = 22). Interestingly, these progenitor species harbour a greater level of genetic variability and are an important source of genes to broaden the narrow Arabica genetic base. Here, we describe the development, evaluation and use of a single-nucleotide polymorphism (SNP) array for coffee trees. A total of 8580 unique and informative SNPs were selected from C. canephora and C. arabica sequencing data, with 40% of the SNP located in annotated genes. In particular, this array contains 227 markers associated to 149 genes and traits of agronomic importance. Among these, 7065 SNPs (~82.3%) were scorable and evenly distributed over the genome with a mean distance of 54.4 Kb between markers. With this array, we improved the Robusta high-density genetic map by adding 1307 SNP markers, whereas 945 SNPs were found segregating in the Arabica mapping progeny. A panel of C. canephora accessions was successfully discriminated and over 70% of the SNP markers were transferable across the three species. Furthermore, the canephora-derived subgenome of C. arabica was shown to be more closely related to C. canephora accessions from northern Uganda than to other current populations. These validated SNP markers and high-density genetic maps will be useful to molecular genetics and for innovative approaches in coffee breeding.


Assuntos
Mapeamento Cromossômico , Coffea/genética , Polimorfismo de Nucleotídeo Único , Marcadores Genéticos , Genoma de Planta , Uganda
4.
J Exp Med ; 215(10): 2567-2585, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30143481

RESUMO

Life-threatening pulmonary influenza can be caused by inborn errors of type I and III IFN immunity. We report a 5-yr-old child with severe pulmonary influenza at 2 yr. She is homozygous for a loss-of-function IRF9 allele. Her cells activate gamma-activated factor (GAF) STAT1 homodimers but not IFN-stimulated gene factor 3 (ISGF3) trimers (STAT1/STAT2/IRF9) in response to IFN-α2b. The transcriptome induced by IFN-α2b in the patient's cells is much narrower than that of control cells; however, induction of a subset of IFN-stimulated gene transcripts remains detectable. In vitro, the patient's cells do not control three respiratory viruses, influenza A virus (IAV), parainfluenza virus (PIV), and respiratory syncytial virus (RSV). These phenotypes are rescued by wild-type IRF9, whereas silencing IRF9 expression in control cells increases viral replication. However, the child has controlled various common viruses in vivo, including respiratory viruses other than IAV. Our findings show that human IRF9- and ISGF3-dependent type I and III IFN responsive pathways are essential for controlling IAV.


Assuntos
Alelos , Homozigoto , Influenza Humana , Fator Gênico 3 Estimulado por Interferon, Subunidade gama/deficiência , Orthomyxoviridae/imunologia , Pneumonia Viral , Feminino , Humanos , Lactente , Influenza Humana/genética , Influenza Humana/imunologia , Influenza Humana/patologia , Interferon alfa-2/genética , Interferon alfa-2/imunologia , Fator Gênico 3 Estimulado por Interferon, Subunidade gama/imunologia , Pneumonia Viral/genética , Pneumonia Viral/imunologia , Pneumonia Viral/patologia
5.
J Clin Invest ; 128(9): 3957-3975, 2018 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-29969437

RESUMO

Biallelic loss-of-function (LOF) mutations of the NCF4 gene, encoding the p40phox subunit of the phagocyte NADPH oxidase, have been described in only 1 patient. We report on 24 p40phox-deficient patients from 12 additional families in 8 countries. These patients display 8 different in-frame or out-of-frame mutations of NCF4 that are homozygous in 11 of the families and compound heterozygous in another. When overexpressed in NB4 neutrophil-like cells and EBV-transformed B cells in vitro, the mutant alleles were found to be LOF, with the exception of the p.R58C and c.120_134del alleles, which were hypomorphic. Particle-induced NADPH oxidase activity was severely impaired in the patients' neutrophils, whereas PMA-induced dihydrorhodamine-1,2,3 (DHR) oxidation, which is widely used as a diagnostic test for chronic granulomatous disease (CGD), was normal or mildly impaired in the patients. Moreover, the NADPH oxidase activity of EBV-transformed B cells was also severely impaired, whereas that of mononuclear phagocytes was normal. Finally, the killing of Candida albicans and Aspergillus fumigatus hyphae by neutrophils was conserved in these patients, unlike in patients with CGD. The patients suffer from hyperinflammation and peripheral infections, but they do not have any of the invasive bacterial or fungal infections seen in CGD. Inherited p40phox deficiency underlies a distinctive condition, resembling a mild, atypical form of CGD.


Assuntos
Doença Granulomatosa Crônica/genética , Mutação com Perda de Função , Fosfoproteínas/deficiência , Fosfoproteínas/genética , Adolescente , Adulto , Alelos , Criança , Pré-Escolar , Feminino , Técnicas de Inativação de Genes , Doença Granulomatosa Crônica/diagnóstico , Doença Granulomatosa Crônica/metabolismo , Células HEK293 , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , Linhagem , Fagócitos/imunologia , Fagócitos/metabolismo , Fagócitos/microbiologia , Fenótipo , Fosfoproteínas/metabolismo , Prognóstico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução Genética , Adulto Jovem
6.
Sci Immunol ; 3(24)2018 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-29907691

RESUMO

Heterozygosity for human signal transducer and activator of transcription 3 (STAT3) dominant-negative (DN) mutations underlies an autosomal dominant form of hyper-immunoglobulin E syndrome (HIES). We describe patients with an autosomal recessive form of HIES due to loss-of-function mutations of a previously uncharacterized gene, ZNF341 ZNF341 is a transcription factor that resides in the nucleus, where it binds a specific DNA motif present in various genes, including the STAT3 promoter. The patients' cells have low basal levels of STAT3 mRNA and protein. The autoinduction of STAT3 production, activation, and function by STAT3-activating cytokines is strongly impaired. Like patients with STAT3 DN mutations, ZNF341-deficient patients lack T helper 17 (TH17) cells, have an excess of TH2 cells, and have low memory B cells due to the tight dependence of STAT3 activity on ZNF341 in lymphocytes. Their milder extra-hematopoietic manifestations and stronger inflammatory responses reflect the lower ZNF341 dependence of STAT3 activity in other cell types. Human ZNF341 is essential for the STAT3 transcription-dependent autoinduction and sustained activity of STAT3.


Assuntos
Regulação da Expressão Gênica/imunologia , Síndrome de Job/genética , Fator de Transcrição STAT3/genética , Fatores de Transcrição/genética , Transcrição Genética/imunologia , Adolescente , Adulto , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Núcleo Celular/metabolismo , Consanguinidade , Citocinas/imunologia , Citocinas/metabolismo , Éxons/genética , Feminino , Genes Recessivos/genética , Genes Recessivos/imunologia , Homozigoto , Humanos , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Síndrome de Job/sangue , Síndrome de Job/imunologia , Mutação com Perda de Função , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Linhagem , Regiões Promotoras Genéticas/genética , RNA Mensageiro/metabolismo , Fator de Transcrição STAT3/imunologia , Fator de Transcrição STAT3/metabolismo , Células Th17/imunologia , Células Th17/metabolismo , Células Th2/imunologia , Células Th2/metabolismo , Fatores de Transcrição/imunologia , Fatores de Transcrição/metabolismo , Sequenciamento Completo do Exoma , Adulto Jovem , Dedos de Zinco/genética
7.
Elife ; 72018 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-29537367

RESUMO

Most humans are exposed to Tropheryma whipplei (Tw). Whipple's disease (WD) strikes only a small minority of individuals infected with Tw (<0.01%), whereas asymptomatic chronic carriage is more common (<25%). We studied a multiplex kindred, containing four WD patients and five healthy Tw chronic carriers. We hypothesized that WD displays autosomal dominant (AD) inheritance, with age-dependent incomplete penetrance. We identified a single very rare non-synonymous mutation in the four patients: the private R98W variant of IRF4, a transcription factor involved in immunity. The five Tw carriers were younger, and also heterozygous for R98W. We found that R98W was loss-of-function, modified the transcriptome of heterozygous leukocytes following Tw stimulation, and was not dominant-negative. We also found that only six of the other 153 known non-synonymous IRF4 variants were loss-of-function. Finally, we found that IRF4 had evolved under purifying selection. AD IRF4 deficiency can underlie WD by haploinsufficiency, with age-dependent incomplete penetrance.


Assuntos
Haploinsuficiência/genética , Fatores Reguladores de Interferon/genética , Tropheryma/genética , Doença de Whipple/genética , Idoso , Idoso de 80 Anos ou mais , Feminino , Predisposição Genética para Doença/genética , Humanos , Leucócitos/microbiologia , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , Penetrância , Tropheryma/patogenicidade , Doença de Whipple/microbiologia , Doença de Whipple/patologia
8.
J Clin Immunol ; 38(3): 278-282, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29589181

RESUMO

PURPOSE: Mendelian susceptibility to mycobacterial disease (MSMD) is a rare primary immunodeficiency predisposing congenitally affected individuals to diseases caused by weakly virulent mycobacteria, such as Bacillus Calmette-Guérin (BCG) vaccine strains and environmental mycobacteria. IL-12p40 deficiency is a genetic etiology of MSMD resulting in impaired IL-12- and IL-23-dependent IFN-γ immunity. Most of the reported patients with IL-12p40 deficiency originate from Saudi Arabia (30 of 52) and carry the recurrent IL12B mutation c.315insA (27 of 30). METHODS: Whole-exome sequencing was performed on three patients from two unrelated kindreds from Saudi Arabia with disseminated disease caused by a BCG vaccine substrain. RESULTS: Genetic analysis revealed a homozygous mutation, p.W60X, in exon 3 of the IL12B gene, resulting in complete IL12p40 deficiency. This mutation is recurrent due to a new founder effect. CONCLUSIONS: This report provides evidence for a second founder effect for recurrent mutations of IL12B in Saudi Arabia.


Assuntos
Efeito Fundador , Estudos de Associação Genética , Predisposição Genética para Doença , Subunidade p40 da Interleucina-12/genética , Mutação , Infecções por Mycobacterium/etiologia , Pré-Escolar , Análise Mutacional de DNA , Exoma , Feminino , Humanos , Lactente , Masculino , Infecções por Mycobacterium/diagnóstico , Infecções por Mycobacterium/terapia , Linhagem , Arábia Saudita , Sequenciamento Completo do Exoma
9.
Am J Med Genet A ; 173(7): 1858-1865, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28488400

RESUMO

Chromosome 7 germline macrodeletions have been implicated in human congenital malformations and developmental delays. We herein report a novel heterozygous macrodeletion of 7q34-q36.3 in a 16-year-old girl originally from West Indies. Similar to previously reported cases of germline chromosome 7q terminal deletions, our patient has dental malposition, and developmental (growth and intellectual) delay. Novel phenotypic features include endemic Kaposi sarcoma (KS), furrowed tongue, thoracolumbar scoliosis, and mild mitral valve dysplasia. The occurrence of human herpes virus 8-driven KS, in a child otherwise normally resistant to other infectious agents and without any other tumoral lesion, points to a very selective immunodeficiency. While defects in organogenesis have been described with such macrodeletions, this is the first report of immunodeficiency and cancer predisposition.

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