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2.
Clin Exp Immunol ; 195(2): 202-212, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30307608

RESUMO

Mutations affecting recombination activation genes RAG1 and RAG2 are associated with variable phenotypes, depending on the residual recombinase activity. The aim of this study is to describe a variety of clinical phenotypes in RAG-deficient patients from the highly consanguineous Egyptian population. Thirty-one patients with RAG mutations (from 28 families) were included from 2013 to 2017. On the basis of clinical, immunological and genetic data, patients were subdivided into three groups; classical T- B- severe combined immunodeficiency (SCID), Omenn syndrome (OS) and atypical SCID. Nineteen patients presented with typical T- B- SCID; among these, five patients carried a homozygous RAG2 mutation G35V and five others carried two homozygous RAG2 mutations (T215I and R229Q) that were detected together. Four novel mutations were reported in the T- B- SCID group; three in RAG1 (A565P, N591Pfs*14 and K621E) and one in RAG2 (F29S). Seven patients presented with OS and a novel RAG2 mutation (C419W) was documented in one patient. The atypical SCID group comprised five patients. Two had normal B cell counts; one had a previously undescribed RAG2 mutation (V327D). The other three patients presented with autoimmune cytopaenias and features of combined immunodeficiency and were diagnosed at a relatively late age and with a substantial diagnostic delay; one patient had a novel RAG1 mutation (C335R). PID disorders are frequent among Egyptian children because of the high consanguinity. RAG mutations stand behind several variable phenotypes, including classical SCID, OS, atypical SCID with autoimmunity and T- B+ CID.


Assuntos
Proteínas de Ligação a DNA/genética , Proteínas de Homeodomínio/genética , Proteínas Nucleares/genética , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/patologia , Adolescente , Adulto , Linfócitos B/imunologia , Criança , Consanguinidade , Egito , Feminino , Humanos , Masculino , Técnicas de Diagnóstico Molecular , Linfócitos T/imunologia , Sequenciamento Completo do Exoma , Adulto Jovem
3.
Proc Natl Acad Sci U S A ; 116(3): 970-975, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30591564

RESUMO

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a critical regulator of cell death and inflammation, but its relevance for human disease pathogenesis remains elusive. Studies of monogenic disorders might provide critical insights into disease mechanisms and therapeutic targeting of RIPK1 for common diseases. Here, we report on eight patients from six unrelated pedigrees with biallelic loss-of-function mutations in RIPK1 presenting with primary immunodeficiency and/or intestinal inflammation. Mutations in RIPK1 were associated with reduced NF-κB activity, defective differentiation of T and B cells, increased inflammasome activity, and impaired response to TNFR1-mediated cell death in intestinal epithelial cells. The characterization of RIPK1-deficient patients highlights the essential role of RIPK1 in controlling human immune and intestinal homeostasis, and might have critical implications for therapies targeting RIPK1.


Assuntos
Diferenciação Celular , Imunidade nas Mucosas/genética , Doenças Inflamatórias Intestinais , Mucosa Intestinal , Proteína Serina-Treonina Quinases de Interação com Receptores , Imunodeficiência Combinada Severa , Linfócitos B/imunologia , Linfócitos B/patologia , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Células Epiteliais/imunologia , Células Epiteliais/patologia , Feminino , Células HCT116 , Células HEK293 , Humanos , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/patologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Masculino , Mutação , NF-kappa B/genética , NF-kappa B/imunologia , Proteína Serina-Treonina Quinases de Interação com Receptores/deficiência , Proteína Serina-Treonina Quinases de Interação com Receptores/imunologia , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/patologia , Linfócitos T/imunologia , Linfócitos T/patologia
4.
Pathol Res Pract ; 214(12): 2000-2003, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30287185

RESUMO

Severe combined immunodeficiency disease (SCID) mice with human lepidic adenocarcinoma were established by the intrabronchial implantation of fresh surgically resected specimens. Human pulmonary adenocarcinoma tissue from 16 different cases was transplanted into SCID mice, and SCID mouse tumors were established from four of these cases (25%). Among the four tumors, the tumor cells of two SCID mice showed replacement lepidic growth of mouse alveolar structures accompanied by multiple intrapulmonary lesions. Human lung carcinoma cell lines showing lepidic growth are rare and the xenograft models using the SCID mouse model developed in the current study will be useful for analyzing the growth and/or progression patterns and clinical behavior of lepidic adenocarcinoma, the major histological subtype of human carcinoma of the lung.


Assuntos
Adenocarcinoma/patologia , Neoplasias Pulmonares/patologia , Imunodeficiência Combinada Severa/patologia , Animais , Modelos Animais de Doenças , Humanos , Pulmão/patologia , Camundongos , Camundongos SCID
5.
Blood ; 132(22): 2362-2374, 2018 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-30254128

RESUMO

ARPC1B is a key factor for the assembly and maintenance of the ARP2/3 complex that is involved in actin branching from an existing filament. Germline biallelic mutations in ARPC1B have been recently described in 6 patients with clinical features of combined immunodeficiency (CID), whose neutrophils and platelets but not T lymphocytes were studied. We hypothesized that ARPC1B deficiency may also lead to cytoskeleton and functional defects in T cells. We have identified biallelic mutations in ARPC1B in 6 unrelated patients with early onset disease characterized by severe infections, autoimmune manifestations, and thrombocytopenia. Immunological features included T-cell lymphopenia, low numbers of naïve T cells, and hyper-immunoglobulin E. Alteration in ARPC1B protein structure led to absent/low expression by flow cytometry and confocal microscopy. This molecular defect was associated with the inability of patient-derived T cells to extend an actin-rich lamellipodia upon T-cell receptor (TCR) stimulation and to assemble an immunological synapse. ARPC1B-deficient T cells additionally displayed impaired TCR-mediated proliferation and SDF1-α-directed migration. Gene transfer of ARPC1B in patients' T cells using a lentiviral vector restored both ARPC1B expression and T-cell proliferation in vitro. In 2 of the patients, in vivo somatic reversion restored ARPC1B expression in a fraction of lymphocytes and was associated with a skewed TCR repertoire. In 1 revertant patient, memory CD8+ T cells expressing normal levels of ARPC1B displayed improved T-cell migration. Inherited ARPC1B deficiency therefore alters T-cell cytoskeletal dynamics and functions, contributing to the clinical features of CID.


Assuntos
Complexo 2-3 de Proteínas Relacionadas à Actina/genética , Mutação em Linhagem Germinativa , Síndromes de Imunodeficiência/genética , Linfócitos T/patologia , Complexo 2-3 de Proteínas Relacionadas à Actina/química , Feminino , Homozigoto , Humanos , Síndromes de Imunodeficiência/patologia , Masculino , Modelos Moleculares , Linhagem , Conformação Proteica , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/patologia , Linfócitos T/metabolismo
6.
J Cutan Pathol ; 45(12): 940-943, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30203448

RESUMO

Cutaneous granulomas without detectable infectious etiology rarely occur in children and adults with primary immunodeficiency disorders. These cutaneous granulomas are primarily seen in combined variable immunodeficiency, ataxia-telangiectasia, and severe combined immunodeficiency (SCID) and can emulate the reaction patterns seen in sarcoidosis and granuloma annulare. To date, the literature has described only six cases of non-infectious cutaneous granulomas in SCID. We report an unusual case of cutaneous granuloma, mimicking a sarcoma, in a 40-year old male with recombinase activating gene 1-deficient SCID, who presented with a slow-growing globus mass over the lateral aspect of the right elbow. There was heterogeneous enhancement on MRI, which was concerning for neoplasm but no malignancy was found on frozen or permanent sections. GMS, PAS with diastase, and AFB stains, as well as microbiology cultures, were negative. An AE1/AE3 stain was negative and a CD163 stain highlighted histiocytes. No infectious etiology was identified and histopathology revealed palisaded granulomatous dermatitis, most closely resembling a rheumatoid nodule. Although cutaneous manifestations have been reported in nearly half of primary immunodeficiency disorder cases, non-infectious cutaneous granulomas are exceedingly rare in SCID. To our knowledge, this is the first case report of cutaneous palisaded granulomatous dermatitis mimicking a rheumatoid nodule in a major joint.


Assuntos
Dermatite , Granuloma , Proteínas de Homeodomínio/genética , Nódulo Reumatoide , Imunodeficiência Combinada Severa , Adulto , Dermatite/genética , Dermatite/metabolismo , Dermatite/patologia , Granuloma/genética , Granuloma/metabolismo , Granuloma/patologia , Humanos , Masculino , Nódulo Reumatoide/genética , Nódulo Reumatoide/metabolismo , Nódulo Reumatoide/patologia , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/metabolismo , Imunodeficiência Combinada Severa/patologia
7.
Clin Immunol ; 197: 1-5, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30121298

RESUMO

V(D)J recombination, during which recognition and repair of broken DNA chains are accomplished by non-homologous end joining pathway, is a critical process in B and T cell development.Null mutations of each enzyme or protein of this pathway result in T- B- NK+ severe combined immunodeficiency whereas hypomorphic mutations result in atypical(leaky)severe combined immunodeficiency forms. We present two siblings with PRKDC (Protein Kinase, DNA-Activated, Catalytic Polypeptide) mutation who presented with granulomatous skin lesions and recurrent lung infections. Primary immune deficiencies may initially present with skin findings. Disruption in central and peripheral B-cell tolerance and impaired intrathymic T-cell maturation,a central player in T-cell tolerance, have been identified as the mechanism of autoimmunity and granuloma seen in patients. The variation in clinical phenotypes of patients with PRKDC mutation suggests that additional factors such as modifying genes, epigenetic and environmental factors may affect the severity and clinical phenotype of the disease. Functional studies during the follow-up and evaluation before and after hematopoeitic stem cell transplantation will hopefully increase our knowledge about the autoimmune and inflammatory process of the disease spectrum.


Assuntos
Proteína Quinase Ativada por DNA/genética , Granuloma/genética , Histiocitose de Células não Langerhans/genética , Proteínas Nucleares/genética , Imunodeficiência Combinada Severa/genética , Dermatopatias/genética , Pré-Escolar , Feminino , Granuloma/imunologia , Granuloma/patologia , Transplante de Células-Tronco Hematopoéticas , Histiocitose de Células não Langerhans/imunologia , Histiocitose de Células não Langerhans/patologia , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Lactente , Recém-Nascido , Pneumonia Bacteriana/genética , Pneumonia Bacteriana/imunologia , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/patologia , Imunodeficiência Combinada Severa/terapia , Irmãos , Dermatopatias/imunologia , Dermatopatias/patologia
8.
Blood Adv ; 2(15): 1828-1832, 2018 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-30061307

RESUMO

DNA ligase 4 deficiency (LIG4-SCID) causes lymphopenia (T-B-NK+) and a radiosensitive SCID (RS-SCID) phenotype. We demonstrate, for the first time, flow cytometric-based kinetic analysis of phosphorylated H2AX (γH2AX) in lymphocyte subsets, especially NK cells, for the assessment of LIG4-SCID. Measurement of phosphorylated (p) ATM, SMC1, and H2AX (γH2AX) was performed by flow cytometry to assess DNA repair defects in a 3-year-old girl. Functional assessment (phosphorylation) was measured in T and NK cells (B cells were absent) before irradiation (background control) or after low-dose (2Gy) irradiation (1 and 24 hours). We observed maximal γH2AX at 1 hour postirradiation, with dephosphorylation at 24 hours postirradiation in healthy control patients. The patient showed normal frequencies (percentage) of T cells and NK cells for γH2AX, but increased levels of γH2AX compared with control patients at 1 hour postirradiation. At 24 hours postirradiation, there was a lack of dephosphorylation in a substantial proportion of lymphocytes (with differences observed between T and NK cells) compared with healthy control patients. Although there was dephosphorylation of γH2AX at 24 hours in patient lymphocytes compared with 1 hour, the amount remained elevated at 24 hours compared with in control patients. The data from pATM and pSMC1 were uninformative. Flow-based kinetic analysis of γH2AX is a useful marker for the diagnosis of LIG4-SCID.


Assuntos
DNA Ligase Dependente de ATP/deficiência , Raios gama , Histonas/imunologia , Células Matadoras Naturais , Imunodeficiência Combinada Severa , Linfócitos T , Biomarcadores , DNA Ligase Dependente de ATP/imunologia , Feminino , Citometria de Fluxo , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Fosforilação/imunologia , Tolerância a Radiação/genética , Tolerância a Radiação/imunologia , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/patologia , Linfócitos T/imunologia , Linfócitos T/patologia
9.
Biol Blood Marrow Transplant ; 24(9): 1944-1946, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29753156

RESUMO

Viral infections can be life threatening in patients with severe combined immunodeficiency (SCID) and other forms of profound primary immunodeficiency disorders both before and after hematopoietic stem cell transplantation (HSCT). Adoptive immunotherapy with virus-specific T cells (VSTs) has been utilized in many patients in the setting of HSCT, but has very rarely been attempted for treatment of viral infections before HSCT. Here we describe the use of VSTs in an infant with RAG1 SCID who had developed disseminated adenovirus which failed to improve on cidofovir. Adenovirus cleared following 2 doses of VSTs and marrow infusion from a matched unrelated donor, without incidence of graft versus host disease. T cell receptor-b sequencing demonstrated expansion of adenovirus-specific T cell fraction of the VSTs, suggesting that infusion facilitated viral clearance. This report suggests that VSTs are likely safe in the pre-HSCT period, and may be a useful bridge therapy for infants with SCID and persistent viral infections.


Assuntos
Adenoviridae/patogenicidade , Antivirais/uso terapêutico , Imunodeficiência Combinada Severa/terapia , Viroses/virologia , Antivirais/farmacologia , Feminino , Humanos , Lactente , Masculino , Imunodeficiência Combinada Severa/patologia
11.
Eur J Hum Genet ; 26(7): 960-971, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29681619

RESUMO

Deficiency of adenosine deaminase 2 (DADA2) is a recently described autoinflammatory disorder. Genetic analysis is required to confirm the diagnosis. We aimed to describe the identifying symptoms and genotypes of patients referred to our reference centres and to improve the indications for genetic testing. DNA from 66 patients with clinically suspected DADA2 were sequenced by Sanger or next-generation sequencing. Detailed epidemiological, clinical and biological features were collected by use of a questionnaire and were compared between patients with and without genetic confirmation of DADA2. We identified 13 patients (19.6%) carrying recessively inherited mutations in ADA2 that were predicted to be deleterious. Eight patients were compound heterozygous for mutations. Seven mutations were novel (4 missense variants, 2 predicted to affect mRNA splicing and 1 frameshift). The mean age of the 13 patients with genetic confirmation was 12.7 years at disease onset and 20.8 years at diagnosis. Phenotypic manifestations included fever (85%), vasculitis (85%) and neurological disorders (54%). Features best associated with a confirmatory genotype included fever with neurologic or cutaneous attacks (odds ratio [OR] 10.71, p = 0.003 and OR 10.9, p < 0.001), fever alone (OR 8.1, p = 0.01), and elevated C-reactive protein (CRP) level with neurologic involvement (OR 6.63, p = 0.017). Our proposed decision tree may help improve obtaining genetic confirmation of DADA2 in the context of autoinflammatory symptoms. Prerequisites for quick and low-cost Sanger analysis include one typical cutaneous or neurological sign, one marker of inflammation (fever or elevated CRP level), and recurrent or chronic attacks in adults.


Assuntos
Adenosina Desaminase/deficiência , Agamaglobulinemia/genética , Árvores de Decisões , Inflamação/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Imunodeficiência Combinada Severa/genética , Adenosina Desaminase/sangue , Adenosina Desaminase/genética , Adolescente , Adulto , Agamaglobulinemia/sangue , Agamaglobulinemia/patologia , Proteína C-Reativa/metabolismo , Criança , Pré-Escolar , Feminino , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Inflamação/sangue , Inflamação/patologia , Masculino , Mutação , Fenótipo , Imunodeficiência Combinada Severa/sangue , Imunodeficiência Combinada Severa/patologia , Pele/metabolismo , Pele/patologia , Adulto Jovem
12.
Chem Pharm Bull (Tokyo) ; 66(3): 217-224, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29491255

RESUMO

Despite the critical need for lifelong treatment of inherited and genetic diseases, there are no developmental efforts for most such diseases due to their rarity. Recent progress in gene therapy, including the approvals of two products (Glybera and Strimvelis) that may provide patients with sustained effects, has shed light on the development of gene therapy products. Most gene therapy products are based on either adeno-associated virus-mediated in vivo gene transfer to target tissues or administration of ex vivo gene-transduced hematopoietic cells. In such circumstances, there is room for different approaches to provide clinicians with other therapeutic options through a variety of principles based on studies not only to gain an understanding of the pathological mechanisms of diseases, but also to understand the physiological functions of target tissues and cells. In this review, we summarize recent progress in gene therapy-mediated enzyme replacement and introduce a different approach using adipocytes to enable lifelong treatment for intractable plasma protein deficiencies.


Assuntos
Adipócitos/metabolismo , Doenças Genéticas Inatas/terapia , Adenosina Desaminase/deficiência , Adipócitos/citologia , Adipócitos/transplante , Agamaglobulinemia/patologia , Agamaglobulinemia/terapia , Terapia Baseada em Transplante de Células e Tecidos , Dependovirus/genética , Terapia de Reposição de Enzimas , Fator VIII/genética , Fator VIII/metabolismo , Doenças Genéticas Inatas/patologia , Terapia Genética , Vetores Genéticos/genética , Vetores Genéticos/metabolismo , Hemofilia A/terapia , Humanos , Doenças por Armazenamento dos Lisossomos/terapia , Imunodeficiência Combinada Severa/patologia , Imunodeficiência Combinada Severa/terapia
13.
Biochem Biophys Res Commun ; 497(2): 719-725, 2018 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-29462620

RESUMO

AK2 is an adenylate phosphotransferase that localizes at the intermembrane spaces of the mitochondria, and its mutations cause a severe combined immunodeficiency with neutrophil maturation arrest named reticular dysgenesis (RD). Although the dysfunction of hematopoietic stem cells (HSCs) has been implicated, earlier developmental events that affect the fate of HSCs and/or hematopoietic progenitors have not been reported. Here, we used RD-patient-derived induced pluripotent stem cells (iPSCs) as a model of AK2-deficient human cells. Hematopoietic differentiation from RD-iPSCs was profoundly impaired. RD-iPSC-derived hemoangiogenic progenitor cells (HAPCs) showed decreased ATP distribution in the nucleus and altered global transcriptional profiles. Thus, AK2 has a stage-specific role in maintaining the ATP supply to the nucleus during hematopoietic differentiation, which affects the transcriptional profiles necessary for controlling the fate of multipotential HAPCs. Our data suggest that maintaining the appropriate energy level of each organelle by the intracellular redistribution of ATP is important for controlling the fate of progenitor cells.


Assuntos
Trifosfato de Adenosina/metabolismo , Adenilato Quinase/metabolismo , Hematopoese , Células-Tronco Hematopoéticas/patologia , Células-Tronco Pluripotentes Induzidas/patologia , Leucopenia/patologia , Imunodeficiência Combinada Severa/patologia , Adenilato Quinase/genética , Células Cultivadas , Metabolismo Energético , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Leucopenia/genética , Leucopenia/metabolismo , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/metabolismo , Regulação para Cima
14.
Pediatr Infect Dis J ; 37(4): 356-358, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28938259

RESUMO

Rare cases of extrapulmonary involvement in Legionella spp. infections have been described, mostly in immunocompromised adults. We report a case of a 2-month old male with reticular dysgenesis variant of severe combined immune deficiency with multiple liver lesions. Core-needle biopsies of one liver lesion demonstrated Gram-negative bacilli and a broad-spectrum polymerase chain reaction assay detected Legionella pneumophila.


Assuntos
Hepatite/etiologia , Hepatite/patologia , Legionella pneumophila/isolamento & purificação , Doença dos Legionários/diagnóstico , Doença dos Legionários/patologia , Imunodeficiência Combinada Severa/complicações , Imunodeficiência Combinada Severa/patologia , Biópsia , Histocitoquímica , Humanos , Lactente , Masculino , Microscopia , Reação em Cadeia da Polimerase
15.
Front Immunol ; 9: 2959, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30666249
18.
Clin Immunol ; 183: 198-200, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28917720

RESUMO

JAK3 is a tyrosine kinase essential for signaling downstream of the common gamma chain subunit shared by multiple cytokine receptors. JAK3 deficiency results in T-B+NK- severe combined immune deficiency (SCID). We report a patient with SCID due to a novel mutation in the JAK3 JH4 domain. The function of the JH4 domain remains unknown. This is the first report of a missense mutation in the JAK3 JH4 domain, thereby demonstrating the importance of the JH4 domain of JAK3 in host immunity.


Assuntos
Janus Quinase 3/metabolismo , Osteomielite/genética , Imunodeficiência Combinada Severa/genética , Coluna Vertebral/patologia , Evolução Fatal , Feminino , Humanos , Lactente , Janus Quinase 3/genética , Mutação , Osteomielite/complicações , Domínios Proteicos , Imunodeficiência Combinada Severa/complicações , Imunodeficiência Combinada Severa/patologia
19.
Clin Immunol ; 183: 201-206, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28729231

RESUMO

Non-homologous end-joining (NHEJ) is a pathway that repairs double-strand breaks (DSB) in DNA and plays a vital role in V(D)J recombination of immunoglobulin genes. Cernunnos is a DNA repair factor that is involved in nonhomologous end-joining (NHEJ) process. Impairment in Cernunnos leads to a genetic disease characterized by neural disorders, immunodeficiency and increased radiosensitivity. We herein describe a severe combined immunodeficiency (SCID) patient with T- B+ phenotype who had a mutation in Cernunnos gene and manifested recurrent infections, microcephaly and growth retardation with hypogammaglobulinemia. Furthermore, our patient was associated with BCG adenitis and autoimmunity that less is observed in patients with Cernunnos deficiency. In contrast to previous reported Cernunnos-deficient patients, our patient had normal B-cell number along with normal IgA and IgM, suggesting a leaky form of the Cernunnos deficiency due to residual count of B cells in our patient. Cernunnos deficiency should be considered in children with recurrent bacterial infections, microcephaly and growth retardation, in spite of having normal B-cell as well as normal IgM and IgA level.


Assuntos
Vacina BCG/efeitos adversos , Enzimas Reparadoras do DNA/metabolismo , Proteínas de Ligação a DNA/metabolismo , Linfadenite/etiologia , Imunodeficiência Combinada Severa/genética , Pré-Escolar , Enzimas Reparadoras do DNA/deficiência , Enzimas Reparadoras do DNA/genética , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Irã (Geográfico) , Imunodeficiência Combinada Severa/patologia , Imunodeficiência Combinada Severa/terapia
20.
Immunogenetics ; 69(10): 653-659, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28597365

RESUMO

Severe combined immunodeficiency (SCID) is the most severe form of primary immunodeficiency, which is characterized by the dysfunction and/or absence of T lymphocytes. Early diagnosis of SCID is crucial for overall survival, and if it remains untreated, SCID is often fatal. Next-generation sequencing (NGS) has become a rapid, high-throughput technology, and has already been proven to be beneficial in medical diagnostics. In this study, a targeted NGS panel was developed to identify the genetic variations of SCID by using SmartChip-TE technology, and a novel pathogenic frameshift variant was found in the CD3E gene. Sanger sequencing has confirmed the segregation of the variant among patients. We found a novel deletion in the CD3E gene (NM000733.3:p.L58Hfs*9) in two T-B+ NK+ patients. The variant was not found in the databases of dbSNP, ExAC, and 1000G. One sibling in family I was homozygous and the rest of the family members were heterozygous for this variant. T cell receptor excision circle (TREC) and kappa-deleting recombination excision circle (KREC) analyses were performed for T and B cell maturation. TRECs were not detected in both patients and the KREC copy numbers were similar to the other family members. In addition, heterozygous family members showed decreased TREC levels when compared with the wild-type sibling, indicating that carrying this variant in one allele does not cause immunodeficiency, but does effect T cell proliferation. Here, we report a novel pathogenic frameshift variant in CD3E gene by using targeted NGS panel.


Assuntos
Sequência de Bases , Complexo CD3/genética , Mutação da Fase de Leitura , Deleção de Sequência , Imunodeficiência Combinada Severa/genética , Linfócitos B/imunologia , Linfócitos B/patologia , Complexo CD3/imunologia , Proliferação de Células , Consanguinidade , Feminino , Expressão Gênica , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala , Homozigoto , Humanos , Lactente , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Masculino , Linhagem , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/patologia , Irmãos , Linfócitos T/imunologia , Linfócitos T/patologia , Turquia
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