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1.
J Clin Immunol ; 42(3): 606-617, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35040013

RESUMO

PURPOSE: Enterovirus A71 (EV71) causes a broad spectrum of childhood diseases, ranging from asymptomatic infection or self-limited hand-foot-and-mouth disease (HFMD) to life-threatening encephalitis. The molecular mechanisms underlying these different clinical presentations remain unknown. We hypothesized that EV71 encephalitis in children might reflect an intrinsic host single-gene defect of antiviral immunity. We searched for mutations in the toll-like receptor 3 (TLR3) gene. Such mutations have already been identified in children with herpes simplex virus encephalitis (HSE). METHODS: We sequenced TLR3 and assessed the impact of the mutations identified. We tested dermal fibroblasts from a patient with EV71 encephalitis and a TLR3 mutation and other patients with known genetic defects of TLR3 or related genes, assessing the response of these cells to TLR3 agonist poly(I:C) stimulation and EV71 infection. RESULTS: Three children with EV71 encephalitis were heterozygous for rare mutations-TLR3 W769X, E211K, and R867Q-all of which were shown to affect TLR3 function. Furthermore, fibroblasts from the patient heterozygous for the W769X mutation displayed an impaired, but not abolished, response to poly(I:C). We found that TLR3-deficient and TLR3-heterozygous W769X fibroblasts were highly susceptible to EV71 infection. CONCLUSIONS: Autosomal dominant TLR3 deficiency may underlie severe EV71 infection with encephalitis. Human TLR3 immunity is essential to protect the central nervous system against HSV-1 and EV71. Children with severe EV71 infections, such as encephalitis in particular, should be tested for inborn errors of TLR3 immunity.


Assuntos
Encefalite por Herpes Simples , Encefalite Viral , Enterovirus Humano A , Infecções por Enterovirus , Enterovirus , Células Cultivadas , Criança , Encefalite por Herpes Simples/diagnóstico , Encefalite por Herpes Simples/genética , Encefalite Viral/diagnóstico , Encefalite Viral/genética , Enterovirus Humano A/genética , Infecções por Enterovirus/diagnóstico , Infecções por Enterovirus/genética , Humanos , Poli I-C , Receptor 3 Toll-Like/genética
2.
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.

4.
J Clin Immunol ; 35(5): 486-90, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26044242

RESUMO

Deep dermatophytosis has been described in HIV and immunosuppressed patients. Recently, CARD9 (caspase recruitment domain-containing protein 9) deficiency has been reported in individuals with deep dermatophytosis previously classified as "immunocompetent". We report a 24-year-old Brazilian male patient with deep dermatophytosis born to an apparently non-consanguineous family. The symptoms started with oral candidiasis when he was 3 years old, persistent although treated. At 11 years old, well delimited, desquamative and pruriginous skin lesions appeared in the mandibular area; ketoconazole and itraconazole were introduced and maintained for 5 years. At 12 years of age, the lesions, which initially affected the face, started to spread to thoracic and back of the body (15 cm of diameter) and became ulcerative, secretive and painful. Terbinafine was introduced without any improvement. Trichophyton mentagrophytes was isolated from the skin lesions. A novel homozygous mutation in CARD9 (R101L) was identified in the patient, resulting in impaired neutrophil fungal killing. Both parents, one brother (with persistent superficial but not deep dermatophytosis) and one sister were heterozygous for this mutation, while another brother was found to be homozygous for the CARD9 wild-type allele. This is the first report of CARD9 deficiency in Latin America.


Assuntos
Proteínas Adaptadoras de Sinalização CARD/genética , Candidíase Bucal/diagnóstico , Neutrófilos/fisiologia , Pele/patologia , Tinha/diagnóstico , Adulto , Brasil , Proteínas Adaptadoras de Sinalização CARD/isolamento & purificação , Candidíase Bucal/genética , Criança , Pré-Escolar , Citotoxicidade Imunológica/genética , Feminino , Predisposição Genética para Doença , Homozigoto , Humanos , Masculino , Neutrófilos/microbiologia , Linhagem , Deleção de Sequência/genética , Pele/microbiologia , Tinha/genética , Adulto Jovem
5.
Hum Mutat ; 35(1): 137-46, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24166846

RESUMO

Joubert syndrome (JS) is characterized by a distinctive cerebellar structural defect, namely the << molar tooth sign >>. JS is genetically heterogeneous, involving 20 genes identified to date, which are all required for cilia biogenesis and/or function. In a consanguineous family with JS associated with optic nerve coloboma, kidney hypoplasia, and polydactyly, combined exome sequencing and mapping identified a homozygous splice-site mutation in PDE6D, encoding a prenyl-binding protein. We found that pde6d depletion in zebrafish leads to renal and retinal developmental anomalies and wild-type but not mutant PDE6D is able to rescue this phenotype. Proteomic analysis identified INPP5E, whose mutations also lead to JS or mental retardation, obesity, congenital retinal dystrophy, and micropenis syndromes, as novel prenyl-dependent cargo of PDE6D. Mutant PDE6D shows reduced binding to INPP5E, which fails to localize to primary cilia in patient fibroblasts and tissues. Furthermore, mutant PDE6D is unable to bind to GTP-bound ARL3, which acts as a cargo-release factor for PDE6D-bound INPP5E. Altogether, these results indicate that PDE6D is required for INPP5E ciliary targeting and suggest a broader role for PDE6D in targeting other prenylated proteins to the cilia. This study identifies PDE6D as a novel JS disease gene and provides the first evidence of prenyl-binding-dependent trafficking in ciliopathies.


Assuntos
Doenças Cerebelares/genética , Doenças Cerebelares/metabolismo , Cílios/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 6/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 6/metabolismo , Anormalidades do Olho/genética , Anormalidades do Olho/metabolismo , Doenças Renais Císticas/genética , Doenças Renais Císticas/metabolismo , Monoéster Fosfórico Hidrolases/genética , Monoéster Fosfórico Hidrolases/metabolismo , Retina/anormalidades , Fatores de Ribosilação do ADP/metabolismo , Anormalidades Múltiplas , Animais , Cerebelo/anormalidades , Exoma , Feminino , Predisposição Genética para Doença , Homozigoto , Humanos , Masculino , Modelos Moleculares , Linhagem , Prenilação de Proteína , Proteômica , Retina/metabolismo , Análise de Sequência de DNA , Peixe-Zebra/anormalidades , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
6.
Clin Infect Dis ; 41 Suppl 7: S436-9, 2005 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-16237643

RESUMO

Septicemia is a life-threatening condition that may lead to sepsis and even septic shock. This cascade is usually accompanied by a pronounced inflammatory response, leading to high body temperature and elevated levels of laboratory markers of inflammation. However, this response can be significantly diminished in children with inherited disorders of nuclear factor (NF)-kappa B-mediated immunity. Three disease-causing genes involved in NF-kappa B activation have been identified: NEMO, IKBA, and IRAK4. Patients with anhidrotic ectodermal dysplasia and immunodeficiency, which is caused by mutations in NEMO and IKBA, have sparse hair, dry skin, and conical teeth and are at increased risk of severe infections caused by pyogenic bacteria and atypical mycobacteria. Patients with interleukin-1 receptor-associated kinase-4 deficiency are at increased risk of invasive disease due to pyogenic bacteria. An underlying defect in NF- kappa B activation should be suspected in children with bacterial septicemia accompanied by mild signs of inflammation.


Assuntos
Displasia Ectodérmica/genética , NF-kappa B/genética , Síndrome de Resposta Inflamatória Sistêmica/genética , Humanos , Inflamação , Quinases Associadas a Receptores de Interleucina-1/deficiência , Quinases Associadas a Receptores de Interleucina-1/metabolismo , NF-kappa B/imunologia , Sepse/diagnóstico , Síndrome de Resposta Inflamatória Sistêmica/diagnóstico , Síndrome de Resposta Inflamatória Sistêmica/imunologia
7.
Medicine (Baltimore) ; 91(4): e1-e19, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22751495

RESUMO

Autosomal dominant deficiency of signal transducer and activator of transcription 3 (STAT3) is the main genetic etiology of hyper-immunoglobulin (Ig) E syndrome. We documented the molecular, cellular, and clinical features of 60 patients with heterozygous STAT3 mutations from 47 kindreds followed in France. We identified 11 known and 13 new mutations of STAT3. Low levels of interleukin (IL)-6-dependent phosphorylation and nuclear translocation (or accumulation) of STAT3 were observed in Epstein-Barr virus-transformed B lymphocytes (EBV-B cells) from all STAT3-deficient patients tested. The immunologic phenotype was characterized by high serum IgE levels (96% of the patients), memory B-cell lymphopenia (94.5%), and hypereosinophilia (80%). A low proportion of IL-17A-producing circulating T cells was found in 14 of the 15 patients tested. Mucocutaneous infections were the most frequent, typically caused by Staphylococcus aureus (all patients) and Candida albicans (85%). Up to 90% of the patients had pneumonia, mostly caused by Staph. aureus (31%) or Streptococcus pneumoniae (30%). Recurrent pneumonia was associated with secondary bronchiectasis and pneumatocele (67%), as well as secondary aspergillosis (22%). Up to 92% of the patients had dermatitis and connective tissue abnormalities, with facial dysmorphism (95%), retention of decidual teeth (65%), osteopenia (50%), and hyperextensibility (50%). Four patients developed non-Hodgkin lymphoma. The clinical outcome was favorable, with 56 patients, including 43 adults, still alive at the end of study (mean age, 21 yr; range, 1 mo to 46 yr). Only 4 patients died, 3 from severe bacterial infection (aged 1, 15, and 29 yr, respectively). Antibiotic prophylaxis (90% of patients), antifungal prophylaxis (50%), and IgG infusions (53%) improved patient health, as demonstrated by the large decrease in pneumonia recurrence. Overall, the prognosis of STAT3 deficiency may be considered good, provided that multiple prophylactic measures, including IgG infusions, are implemented.


Assuntos
Hospedeiro Imunocomprometido/genética , Síndrome de Job/epidemiologia , Síndrome de Job/genética , Fator de Transcrição STAT3/deficiência , Fator de Transcrição STAT3/genética , Adolescente , Adulto , Distribuição por Idade , Criança , Pré-Escolar , Estudos Transversais , Análise Mutacional de DNA , Bases de Dados Factuais , Eczema/epidemiologia , Eczema/etiologia , Feminino , França/epidemiologia , Predisposição Genética para Doença/epidemiologia , Heterozigoto , Humanos , Incidência , Lactente , Recém-Nascido , Síndrome de Job/complicações , Síndrome de Job/imunologia , Masculino , Pessoa de Meia-Idade , Fosforilação , Pneumonia Bacteriana/epidemiologia , Pneumonia Bacteriana/etiologia , Infecções Respiratórias/epidemiologia , Infecções Respiratórias/etiologia , Medição de Risco , Índice de Gravidade de Doença , Distribuição por Sexo , Transdução de Sinais , Dermatopatias Bacterianas/epidemiologia , Dermatopatias Bacterianas/etiologia , Infecções Estafilocócicas/epidemiologia , Infecções Estafilocócicas/etiologia , Análise de Sobrevida , Adulto Jovem
8.
Pediatrics ; 115(5): e615-9, 2005 May.
Artigo em Inglês | MEDLINE | ID: mdl-15833888

RESUMO

X-linked recessive anhidrotic ectodermal dysplasia with immunodeficiency is a developmental and immunologic disorder caused by mutations in nuclear factor-kappaB essential modulator (NEMO), which is essential for nuclear factor-kappaB activation. Early in life, affected boys present a typical appearance, with hypotrichosis or atrichosis, hypohidrosis or anhidrosis, and hypodontia or anodontia with conical incisors. They are also susceptible to various microorganisms, mostly pyogenic bacteria and mycobacteria. Here we report 2 unrelated boys, aged 6 and 11 years, who have novel mutations in NEMO and present conical incisors and hypodontia as their sole and long-unrecognized developmental anomaly. One child had isolated recurrent pneumococcal disease, whereas the other had multiple infections. Our observations indicate that conical incisors should prompt the search for NEMO mutations in boys with unusual infectious diseases.


Assuntos
Displasia Ectodérmica/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Síndromes de Imunodeficiência/genética , Proteínas Serina-Treonina Quinases/genética , Anormalidades Dentárias/genética , Anodontia/genética , Infecções Bacterianas/etiologia , Criança , Humanos , Quinase I-kappa B , Imunoglobulinas/sangue , Masculino , Mutação
9.
Pediatrics ; 109(6): e97, 2002 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12042591

RESUMO

A child with X-linked osteopetrosis, lymphedema, anhidrotic ectodermal dysplasia, and immunodeficiency (OL-EDA-ID) was recently reported. We report the clinical features of a second boy with this novel syndrome and his mother, who presented with signs of incontinentia pigmenti (IP). The child had mild osteopetrosis without neurosensory complications, unilateral lymphedema of the left leg, and characteristic features of anhidrotic ectodermal dysplasia with sparse hair, facial dysmorphy, delayed eruption of teeth, and sweat gland abnormalities. He died at 18 months of severe immunodeficiency with multiple infections caused by Gram-negative (Salmonella enteritidis) and Gram-positive (Streptococcus pneumoniae) bacteria, nontuberculous mycobacteria (Mycobacterium kansasii), and fungi (Pneumocystis carinii). His 30-year-old mother's medical history, together with residual cutaneous lesions, was highly suggestive of IP without neurologic impairment. In this patient with OL-EDA-ID, we detected the same NF-kappaB essential modulator stop codon hypomorphic mutation identified in the previous patient. The occurrence of the same clinical features in 2 unrelated patients with the same genotype demonstrates that OL-EDA-ID is a genuine clinical syndrome. The clinical and biological descriptions of the proband and his mother further corroborate the relationship between IP and EDA. Both syndromes are allelic and are associated with mutations in NF-kappaB essential modulator, with a genotype-phenotype correlation in hemizygous males. In contrast, loss-of-function mutations and hypomorphic mutations may cause IP in females.


Assuntos
Displasia Ectodérmica/genética , Síndromes de Imunodeficiência/genética , Incontinência Pigmentar/genética , Linfedema/genética , Osteopetrose/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Adulto , Fatores Etários , Códon de Terminação/genética , Displasia Ectodérmica/diagnóstico , Humanos , Quinase I-kappa B , Síndromes de Imunodeficiência/diagnóstico , Incontinência Pigmentar/diagnóstico , Lactente , Recém-Nascido , Linfedema/diagnóstico , Masculino , Mutação/genética , NF-kappa B/genética , Osteopetrose/diagnóstico , Proteínas Serina-Treonina Quinases/genética , Fatores Sexuais , Síndrome
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