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1.
J Exp Med ; 216(9): 2057-2070, 2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31270247

RESUMO

Vaccination against measles, mumps, and rubella (MMR) and yellow fever (YF) with live attenuated viruses can rarely cause life-threatening disease. Severe illness by MMR vaccines can be caused by inborn errors of type I and/or III interferon (IFN) immunity (mutations in IFNAR2, STAT1, or STAT2). Adverse reactions to the YF vaccine have remained unexplained. We report two otherwise healthy patients, a 9-yr-old boy in Iran with severe measles vaccine disease at 1 yr and a 14-yr-old girl in Brazil with viscerotropic disease caused by the YF vaccine at 12 yr. The Iranian patient is homozygous and the Brazilian patient compound heterozygous for loss-of-function IFNAR1 variations. Patient-derived fibroblasts are susceptible to viruses, including the YF and measles virus vaccine strains, in the absence or presence of exogenous type I IFN. The patients' fibroblast phenotypes are rescued with WT IFNAR1 Autosomal recessive, complete IFNAR1 deficiency can result in life-threatening complications of vaccination with live attenuated measles and YF viruses in previously healthy individuals.

2.
J Exp Med ; 216(9): 2038-2056, 2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31217193

RESUMO

Autosomal recessive IRF7 and IRF9 deficiencies impair type I and III IFN immunity and underlie severe influenza pneumonitis. We report three unrelated children with influenza A virus (IAV) infection manifesting as acute respiratory distress syndrome (IAV-ARDS), heterozygous for rare TLR3 variants (P554S in two patients and P680L in the third) causing autosomal dominant (AD) TLR3 deficiency. AD TLR3 deficiency can underlie herpes simplex virus-1 (HSV-1) encephalitis (HSE) by impairing cortical neuron-intrinsic type I IFN immunity to HSV-1. TLR3-mutated leukocytes produce normal levels of IFNs in response to IAV. In contrast, TLR3-mutated fibroblasts produce lower levels of IFN-ß and -λ, and display enhanced viral susceptibility, upon IAV infection. Moreover, the patients' iPSC-derived pulmonary epithelial cells (PECs) are susceptible to IAV. Treatment with IFN-α2b or IFN-λ1 rescues this phenotype. AD TLR3 deficiency may thus underlie IAV-ARDS by impairing TLR3-dependent, type I and/or III IFN-mediated, PEC-intrinsic immunity. Its clinical penetrance is incomplete for both IAV-ARDS and HSE, consistent with their typically sporadic nature.

3.
Curr Opin Immunol ; 59: 88-100, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31121434

RESUMO

Studies of vertebrate immunity have traditionally focused on professional cells, including circulating and tissue-resident leukocytes. Evidence that non-professional cells are also intrinsically essential (i.e. not via their effect on leukocytes) for protective immunity in natural conditions of infection has emerged from three lines of research in human genetics. First, studies of Mendelian resistance to infection have revealed an essential role of DARC-expressing erythrocytes in protection against Plasmodium vivax infection, and an essential role of FUT2-expressing intestinal epithelial cells for protection against norovirus and rotavirus infections. Second, studies of inborn errors of non-hematopoietic cell-extrinsic immunity have shown that APOL1 and complement cascade components secreted by hepatocytes are essential for protective immunity to trypanosome and pyogenic bacteria, respectively. Third, studies of inborn errors of non-hematopoietic cell-intrinsic immunity have suggested that keratinocytes, pulmonary epithelial cells, and cortical neurons are essential for tissue-specific protective immunity to human papillomaviruses, influenza virus, and herpes simplex virus, respectively. Various other types of genetic resistance or predisposition to infection in human populations are not readily explained by inborn variants of genes operating in leukocytes and may, therefore, involve defects in other cells. The probing of this unchartered territory by human genetics is reshaping immunology, by scaling immunity to infection up from the immune system to the whole organism.

4.
Bioinformatics ; 34(24): 4307-4309, 2018 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-30535305

RESUMO

Summary: Next-generation sequencing (NGS) generates large amounts of genomic data and reveals about 20 000 genetic coding variants per individual studied. Several mutation damage prediction scores are available to prioritize variants, but there is currently no application to help investigators to determine the relevance of the candidate genes and variants quickly and visually from population genetics data and deleteriousness scores. Here, we present PopViz, a user-friendly, rapid, interactive, mobile-compatible webserver providing a gene-centric visualization of the variants of any human gene, with (i) population-specific minor allele frequencies from the gnomAD population genetic database; (ii) mutation damage prediction scores from CADD, EIGEN and LINSIGHT and (iii) amino-acid positions and protein domains. This application will be particularly useful in investigations of NGS data for new disease-causing genes and variants, by reinforcing or rejecting the plausibility of the candidate genes, and by selecting and prioritizing, the candidate variants for experimental testing. Availability and implementation: PopViz webserver is freely accessible from http://shiva.rockefeller.edu/PopViz/. Supplementary information: Supplementary data are available at Bioinformatics online.


Assuntos
Frequência do Gene , Variação Genética , Software , Biologia Computacional , Genômica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos
6.
Neurol Neuroimmunol Neuroinflamm ; 5(6): e500, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30211253

RESUMO

Objective: Deficiency in the cytosolic DNA sensor RNA Polymerase III (POL III) was recently described in children with severe varicella-zoster virus (VZV) infection in the CNS or lungs. Here, we describe a pair of monozygotic female twins, who both experienced severe recurrent CNS vasculitis caused by VZV reactivation. The clinical presentation and findings included recurrent episodes of headache, dizziness, and neurologic deficits, CSF with pleocytosis and intrathecal VZV antibody production, and MRI of the brain showing ischemic lesions. Methods: We performed whole-exome sequencing and identified a rare mutation in the POL III subunit POLR3F. Subsequently, antiviral responses in patient peripheral blood mononuclear cells (PBMCs) were examined and compared with healthy controls. Results: The identified R50W POLR3F mutation is predicted by bioinformatics to be damaging, and when tested in functional assays, patient PBMCs exhibited impaired antiviral and inflammatory responses to the POL III agonist poly(dA:dT) and increased viral replication compared with controls. Conclusions: Altogether, these cases add genetic and immunologic evidence to the novel association between defects in sensing of AT-rich DNA present in the VZV genome and increased susceptibility to severe manifestations of VZV infection in the CNS in humans.

7.
J Exp Med ; 215(10): 2567-2585, 2018 Oct 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.

8.
Proc Natl Acad Sci U S A ; 115(37): E8775-E8782, 2018 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-30154162

RESUMO

Herpes simplex virus type 1 (HSV-1) encephalitis (HSE) is the most common sporadic viral encephalitis in Western countries. Some HSE children carry inborn errors of the Toll-like receptor 3 (TLR3)-dependent IFN-α/ß- and -λ-inducing pathway. Induced pluripotent stem cell (iPSC)-derived cortical neurons with TLR3 pathway mutations are highly susceptible to HSV-1, due to impairment of cell-intrinsic TLR3-IFN immunity. In contrast, the contribution of cell-intrinsic immunity of human trigeminal ganglion (TG) neurons remains unclear. Here, we describe efficient in vitro derivation and purification of TG neurons from human iPSCs via a cranial placode intermediate. The resulting TG neurons are of sensory identity and exhibit robust responses to heat (capsaicin), cold (icilin), and inflammatory pain (ATP). Unlike control cortical neurons, both control and TLR3-deficient TG neurons were highly susceptible to HSV-1. However, pretreatment of control TG neurons with poly(I:C) induced the cells into an anti-HSV-1 state. Moreover, both control and TLR3-deficient TG neurons developed resistance to HSV-1 following pretreatment with IFN-ß but not IFN-λ. These data indicate that TG neurons are vulnerable to HSV-1 because they require preemptive stimulation of the TLR3 or IFN-α/ß receptors to induce antiviral immunity, whereas cortical neurons possess a TLR3-dependent constitutive resistance that is sufficient to block incoming HSV-1 in the absence of prior antiviral signals. The lack of constitutive resistance in TG neurons in vitro is consistent with their exploitation as a latent virus reservoir in vivo. Our results incriminate deficiencies in the constitutive TLR3-dependent response of cortical neurons in the pathogenesis of HSE.


Assuntos
Imunidade/imunologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Neurônios/metabolismo , Receptor 3 Toll-Like/metabolismo , Antivirais/farmacologia , Diferenciação Celular/genética , Células Cultivadas , Córtex Cerebral/citologia , Criança , Herpesvirus Humano 1/imunologia , Herpesvirus Humano 1/fisiologia , Humanos , Imunidade/genética , Células-Tronco Pluripotentes Induzidas/citologia , Interferon beta/farmacologia , Mutação , Neurônios/efeitos dos fármacos , Neurônios/virologia , Poli I-C/farmacologia , Receptor 3 Toll-Like/genética , Gânglio Trigeminal/citologia
9.
J Clin Immunol ; 2018 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-29882021

RESUMO

The pathogenesis of life-threatening influenza A virus (IAV) disease remains elusive, as infection is benign in most individuals. We studied two relatives who died from influenza. We Sanger sequenced GATA2 and evaluated the mutation by gene transfer, measured serum cytokine levels, and analyzed circulating T- and B-cells. Both patients (father and son, P1 and P2) died in 2011 of H1N1pdm IAV infection at the ages of 54 and 31 years, respectively. They had not suffered from severe or moderately severe infections in the last 17 (P1) and 15 years (P2). A daughter of P1 had died at 20 years from infectious complications. Low B-cell, NK- cell, and monocyte numbers and myelodysplastic syndrome led to sequence GATA2. Patients were heterozygous for a novel, hypomorphic, R396L mutation leading to haplo-insufficiency. B- and T-cell rearrangement in peripheral blood from P1 during the influenza episode showed expansion of one major clone. No T-cell receptor excision circles were detected in P1 and P3 since they were 35 and 18 years, respectively. Both patients presented an exuberant, interferon (IFN)-γ-mediated hypercytokinemia during H1N1pdm infection. No data about patients with viremia was available. Two previously reported adult GATA2-deficient patients died from severe H1N1 IAV infection; GATA2 deficiency may predispose to life-threatening influenza in adulthood. However, a role of other genetic variants involved in immune responses cannot be ruled out. Patients with GATA2 deficiency can reach young adulthood without severe infections, including influenza, despite long-lasting complete B-cell and natural killer (NK) cell deficiency, as well as profoundly diminished T-cell thymic output.

10.
Cell ; 172(5): 952-965.e18, 2018 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-29474921

RESUMO

Viruses that are typically benign sometimes invade the brainstem in otherwise healthy children. We report bi-allelic DBR1 mutations in unrelated patients from different ethnicities, each of whom had brainstem infection due to herpes simplex virus 1 (HSV1), influenza virus, or norovirus. DBR1 encodes the only known RNA lariat debranching enzyme. We show that DBR1 expression is ubiquitous, but strongest in the spinal cord and brainstem. We also show that all DBR1 mutant alleles are severely hypomorphic, in terms of expression and function. The fibroblasts of DBR1-mutated patients contain higher RNA lariat levels than control cells, this difference becoming even more marked during HSV1 infection. Finally, we show that the patients' fibroblasts are highly susceptible to HSV1. RNA lariat accumulation and viral susceptibility are rescued by wild-type DBR1. Autosomal recessive, partial DBR1 deficiency underlies viral infection of the brainstem in humans through the disruption of tissue-specific and cell-intrinsic immunity to viruses.

11.
J Clin Invest ; 127(9): 3543-3556, 2017 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-28783042

RESUMO

Varicella zoster virus (VZV) typically causes chickenpox upon primary infection. In rare cases, VZV can give rise to life-threatening disease in otherwise healthy people, but the immunological basis for this remains unexplained. We report 4 cases of acute severe VZV infection affecting the central nervous system or the lungs in unrelated, otherwise healthy children who are heterozygous for rare missense mutations in POLR3A (one patient), POLR3C (one patient), or both (two patients). POLR3A and POLR3C encode subunits of RNA polymerase III. Leukocytes from all 4 patients tested exhibited poor IFN induction in response to synthetic or VZV-derived DNA. Moreover, leukocytes from 3 of the patients displayed defective IFN production upon VZV infection and reduced control of VZV replication. These phenotypes were rescued by transduction with relevant WT alleles. This work demonstrates that monogenic or digenic POLR3A and POLR3C deficiencies confer increased susceptibility to severe VZV disease in otherwise healthy children, providing evidence for an essential role of a DNA sensor in human immunity.


Assuntos
Varicela/genética , Herpes Zoster/genética , Mutação , RNA Polimerase III/genética , RNA Polimerase III/metabolismo , Alelos , Animais , Criança , Análise Mutacional de DNA , Regulação Enzimológica da Expressão Gênica , Células HEK293 , Herpesvirus Humano 3 , Heterozigoto , Humanos , Leucócitos/metabolismo , Camundongos , Mutação de Sentido Incorreto , Fenótipo
12.
Pediatr Infect Dis J ; 36(8): 741-744, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28471862

RESUMO

BACKGROUND: Herpes simplex encephalitis (HSE) after primary herpes simplex virus (HSV)-1 infection can occur in children due to inborn errors of cell-intrinsic immunity in the central nervous system. Paradoxically, symptomatic mucocutaneous HSV-1 recurrences are rare survivors of childhood HSE. T-cell-acquired immunity is thought to be involved in control of recurrent mucocutaneous HSV infection. We thus tested HSV-1-specific immunity in HSE survivors. METHODS: We obtained serum and peripheral blood mononuclear cells (PBMCs) from participants a median of 13.5 years after HSE. HSV-1 and HSV-2 IgG was detected by type-specific immunoblot. PBMCs from subjects passing quality control criteria were tested using enzyme-linked immunospot assay for CD4 interferon-γ responses with an HSV-1 lysate and for CD8 responses using pooled synthetic HSV-1 peptide CD8 T-cell epitopes. Healthy adult PBMCs were used to standardize assays and as comparators. RESULTS: All participants were HSV-1 seropositive. Most (23/24) HSE survivors had human leukocyte antigen class I types matching the human leukocyte antigen restriction of the pooled peptides. We detected HSV-specific CD8 T-cell responses in 14 of 24 (58%) HSE survivors and in 9 of 9 healthy HSV-1 seropositive adults. HSV-specific CD4 T-cell responses were present in all 5 HSE subjects tested and in 8 of 9 healthy adults. Response magnitudes were overlapping between subject groups. CONCLUSIONS: The defects in cell-intrinsic immunity leading to failure to control primary central nervous system HSV-1 infection do not preclude the acquisition of specific immunity or the control of recurrent mucocutaneous HSV infections. The rarity and lack of severe or recurrent mucocutaneous HSV infection in survivors of childhood HSE corresponds with intact adaptive T-cell immunity.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Encefalite por Herpes Simples/imunologia , Herpesvirus Humano 1/imunologia , Adolescente , Linfócitos T CD4-Positivos/imunologia , Criança , Pré-Escolar , Estudos de Coortes , ELISPOT , Epitopos/imunologia , Humanos , Lactente , Proteínas Virais/imunologia
13.
J Am Coll Cardiol ; 69(13): 1653-1665, 2017 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-28359509

RESUMO

BACKGROUND: Myocarditis is inflammation of the heart muscle that can follow various viral infections. Why children only rarely develop life-threatening acute viral myocarditis (AVM), given that the causal viral infections are common, is unknown. Genetic lesions might underlie such susceptibilities. Mouse genetic studies demonstrated that interferon (IFN)-α/ß immunity defects increased susceptibility to virus-induced myocarditis. Moreover, variations in human TLR3, a potent inducer of IFNs, were proposed to underlie AVM. OBJECTIVES: This study sought to evaluate the hypothesis that human genetic factors may underlie AVM in previously healthy children. METHODS: We tested the role of TLR3-IFN immunity using human induced pluripotent stem cell-derived cardiomyocytes. We then performed whole-exome sequencing of 42 unrelated children with acute myocarditis (AM), some with proven viral causes. RESULTS: We found that TLR3- and STAT1-deficient cardiomyocytes were not more susceptible to Coxsackie virus B3 (CVB3) infection than control cells. Moreover, CVB3 did not induce IFN-α/ß and IFN-α/ß-stimulated genes in control cardiomyocytes. Finally, exogenous IFN-α did not substantially protect cardiomyocytes against CVB3. We did not observe a significant enrichment of rare variations in TLR3- or IFN-α/ß-related genes. Surprisingly, we found that homozygous but not heterozygous rare variants in genes associated with inherited cardiomyopathies were significantly enriched in AM-AVM patients compared with healthy individuals (p = 2.22E-03) or patients with other diseases (p = 1.08E-04). Seven of 42 patients (16.7%) carried rare biallelic (homozygous or compound heterozygous) nonsynonymous or splice-site variations in 6 cardiomyopathy-associated genes (BAG3, DSP, PKP2, RYR2, SCN5A, or TNNI3). CONCLUSIONS: Previously silent recessive defects of the myocardium may predispose to acute heart failure presenting as AM, notably after common viral infections in children.


Assuntos
Cardiomiopatias/genética , Enterovirus Humano B/fisiologia , Miocardite/genética , Fator de Transcrição STAT1/genética , Receptor 3 Toll-Like/genética , Cardiomiopatias/complicações , Estudos de Casos e Controles , Feminino , Interações Hospedeiro-Patógeno/genética , Humanos , Células-Tronco Pluripotentes Induzidas , Masculino , Miocardite/virologia , Miócitos Cardíacos/virologia
15.
Trends Mol Med ; 22(6): 511-527, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27211305

RESUMO

The importance of TANK binding kinase-1 (TBK1), a multimeric kinase that modulates inflammation and autophagy, in human health has been highlighted for the first time by the recent discoveries of mutations in TBK1 that underlie amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), normal tension glaucoma (NTG) or childhood herpes simplex encephalitis (HSE). Gain-of-function of TBK1 are associated with NTG, whereas loss-of-function mutations result in ALS/FTD or in HSE. In light of these new findings, we review the role of TBK1 in these seemingly unrelated, yet allelic diseases, and discuss the role of TBK1 in neuroinflammatory diseases. This discovery has the potential to significantly increase our understanding of the molecular basis of these poorly understood diseases.


Assuntos
Esclerose Amiotrófica Lateral/metabolismo , Sistema Nervoso Central/metabolismo , Encefalite por Herpes Simples/metabolismo , Demência Frontotemporal/metabolismo , Inflamação/metabolismo , Glaucoma de Baixa Tensão/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/imunologia , Autofagia , Progressão da Doença , Encefalite por Herpes Simples/genética , Encefalite por Herpes Simples/imunologia , Demência Frontotemporal/genética , Expressão Gênica , Humanos , Interferons/imunologia , Interferons/metabolismo , Glaucoma de Baixa Tensão/genética , Glaucoma de Baixa Tensão/imunologia , Mutação , Proteínas Serina-Treonina Quinases/genética
17.
Cell ; 164(3): 564-78, 2016 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-26824662

RESUMO

Type 1 interferon (IFN) is a key mediator of organismal responses to pathogens, eliciting prototypical "interferon signature genes" that encode antiviral and inflammatory mediators. For a global view of IFN signatures and regulatory pathways, we performed gene expression and chromatin analyses of the IFN-induced response across a range of immunocyte lineages. These distinguished ISGs by cell-type specificity, kinetics, and sensitivity to tonic IFN and revealed underlying changes in chromatin configuration. We combined 1,398 human and mouse datasets to computationally infer ISG modules and their regulators, validated by genetic analysis in both species. Some ISGs are controlled by Stat1/2 and Irf9 and the ISRE DNA motif, but others appeared dependent on non-canonical factors. This regulatory framework helped to interpret JAK1 blockade pharmacology, different clusters being affected under tonic or IFN-stimulated conditions, and the IFN signatures previously associated with human diseases, revealing unrecognized subtleties in disease footprints, as affected by human ancestry.


Assuntos
Redes Reguladoras de Genes , Interferon Tipo I/imunologia , Interferon Tipo I/metabolismo , Animais , Linfócitos T CD4-Positivos/metabolismo , Conjuntos de Dados como Assunto , Humanos , Janus Quinases/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Receptor de Interferon alfa e beta/metabolismo
18.
Curr Opin Immunol ; 38: 109-20, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26761402

RESUMO

Influenza viruses cause mild to moderate respiratory illness in most people, and only rarely devastating or fatal infections. The virulence factors encoded by viral genes can explain seasonal or geographic differences at the population level but are unlikely to account for inter-individual clinical variability. Inherited or acquired immunodeficiencies may thus underlie severe cases of influenza. The crucial role of host genes was first demonstrated by forward genetics in inbred mice, with the identification of interferon (IFN)-α/ß-inducible Mx1 as a canonical influenza susceptibility gene. Reverse genetics has subsequently characterized the in vivo role of other mouse genes involved in IFN-α/ß and -λ immunity. A series of in vitro studies with mouse and human cells have also refined the cell-intrinsic mechanisms of protection against influenza viruses. Population-based human genetic studies have not yet uncovered variants with a significant impact. Interestingly, human primary immunodeficiencies affecting T and B cells were also not found to predispose to severe influenza. Recently however, human IRF7 was shown to be essential for IFN-α/ß- and IFN-λ-dependent protective immunity against primary influenza in vivo, as inferred from a patient with life-threatening influenza revealed to be IRF7-deficient by whole exome sequencing. Next generation sequencing of human exomes and genomes will facilitate the analysis of the human genetic determinism of severe influenza.


Assuntos
Imunidade Inata , Hospedeiro Imunocomprometido , Influenza Humana/imunologia , Fator Regulador 7 de Interferon/imunologia , Proteínas de Resistência a Myxovirus/imunologia , Orthomyxoviridae/imunologia , Animais , Citocinas/genética , Citocinas/imunologia , Suscetibilidade a Doenças , Regulação da Expressão Gênica , Humanos , Influenza Humana/genética , Influenza Humana/patologia , Fator Regulador 7 de Interferon/deficiência , Fator Regulador 7 de Interferon/genética , Interferon-alfa/genética , Interferon-alfa/imunologia , Interferon beta/genética , Interferon beta/imunologia , Camundongos , Camundongos Transgênicos , Proteínas de Resistência a Myxovirus/deficiência , Proteínas de Resistência a Myxovirus/genética , Orthomyxoviridae/patogenicidade , Transdução de Sinais
19.
Proc Natl Acad Sci U S A ; 112(44): 13615-20, 2015 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-26483451

RESUMO

The protein-coding exome of a patient with a monogenic disease contains about 20,000 variants, only one or two of which are disease causing. We found that 58% of rare variants in the protein-coding exome of the general population are located in only 2% of the genes. Prompted by this observation, we aimed to develop a gene-level approach for predicting whether a given human protein-coding gene is likely to harbor disease-causing mutations. To this end, we derived the gene damage index (GDI): a genome-wide, gene-level metric of the mutational damage that has accumulated in the general population. We found that the GDI was correlated with selective evolutionary pressure, protein complexity, coding sequence length, and the number of paralogs. We compared GDI with the leading gene-level approaches, genic intolerance, and de novo excess, and demonstrated that GDI performed best for the detection of false positives (i.e., removing exome variants in genes irrelevant to disease), whereas genic intolerance and de novo excess performed better for the detection of true positives (i.e., assessing de novo mutations in genes likely to be disease causing). The GDI server, data, and software are freely available to noncommercial users from lab.rockefeller.edu/casanova/GDI.


Assuntos
Exoma , Doenças Genéticas Inatas/genética , Humanos , Curva ROC
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