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Objective To investigate the role of ataxia-telangiectasia mutated gene (ATM) in maintaining quiescence of neural stem cells (NSCs) from subgranular zone (SGZ) of hippocampal dentate gyms in mice. Methods We constructed 1-month-old and 4-month-old mice ATM knockout mice, with 12 mice in each group. The NSCs in SGZ of ATM knockout mice were isolated, cultured and identified in vitro. The proliferation ability of NSCs in SGZ of 1-month-old ATM
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Genomic instability remains an enabling feature of cancer and promotes malignant transformation. Alterations of DNA damage response (DDR) pathways allow genomic instability, generate neoantigens, upregulate the expression of programmed death ligand 1 (PD-L1) and interact with signaling such as cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling. Here, we review the basic knowledge of DDR pathways, mechanisms of genomic instability induced by DDR alterations, impacts of DDR alterations on immune system, and the potential applications of DDR alterations as biomarkers and therapeutic targets in cancer immunotherapy.
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Ataxia-telangiectasia (AT) is a rare autosomal recessive genetic disorder resulting from ataxia-telangiectasia mutated(ATM) gene mutation.ATM involved in DNA repair.ATM is made up of 66 exons.Its mutation forms are complex, including nonsense mutation, missense mutation, shear site mutation, insertion and deletion, etc.The patients are characterized by progressive cerebellar atrophy and ataxia, disturbance of eye movement, telangiectasia and dystonia, a high risk of cancer and immunodeficiency.These patients are also hypersensitive to radiotherapy.AT is often neglected at the early stage.As pediatricians, we should pay attention to early ataxia and conduct genetic testing as early as possible to avoid radiation exposure.
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Ataxia-telangiectasia (AT) is a rare autosomal recessive genetic disorder resulting from ataxia-telangiectasia mutated (ATM) gene mutation.ATM involved in DNA repair.ATM is made up of 66 exons.Its mutation forms are complex,including nonsense mutation,missense mutation,shear site mutation,insertion and deletion,etc.The patients are characterized by progressive cerebellar atrophy and ataxia,disturbance of eye movement,telangiectasia and dystonia,a high risk of cancer and immunodeficiency.These patients are also hypersensitive to radiotherapy.AT is often neglected at the early stage.As pediatricians,we should pay attention to early ataxia and conduct genetic testing as early as possible to avoid radiation exposure.
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La ataxia-telangiectasia es un trastorno autosómico recesivo, caracterizado por la presencia de telangiectasias oculocutáneas, ataxia cerebelosa progresiva, inmunodeficiencia e infecciones recurrentes. Además, está relacionado con neoplasias del sistema retículo-endotelial y trastornos inmunológicos. El objetivo de la presentación es destacar el papel del dermatólogo en este tipo de trastornos neurocutáneos, así como la importancia del seguimiento a largo plazo.
Ataxia telangiectasia is an autosomal recessive disorder characterized by oculocutaneous telangiectasia, progressive cerebellar ataxia, immunodeficiency, and recurrent infections. Besides, it is related to reticuloendothelial system neoplasms and immune disorders. The aim of this presentation is to emphasize the role of the Dermatologist in this type of neurocutaneous disorders and the importance of long-term follow up.
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Humans , Adolescent , Ataxia Telangiectasia , Neurocutaneous Syndromes , Immunologic Deficiency SyndromesABSTRACT
BACKGROUND AND PURPOSE: Autosomal recessive cerebellar ataxias constitute a highly heterogeneous group of neurodegenerative disorders. This study was carried out to determine the clinical and genetic causes of ataxia in two families from Pakistan. METHODS: Detailed clinical investigations were carried out on probands in two consanguineous families. Magnetic resonance imaging was performed. Exome sequencing data were examined for likely pathogenic variants. Candidate variants were checked for cosegregation with the phenotype using Sanger sequencing. Public databases including ExAC, GnomAD, dbSNP, and the 1,000 Genome Project as well as ethnically matched controls were checked to determine the frequencies of the alleles. Conservation of missense variants was ensured by aligning orthologous protein sequences from diverse vertebrate species. RESULTS: Reverse phenotyping identified spinocerebellar ataxia, autosomal recessive 1 [OMIM 606002, also referred to as ataxia oculomotor apraxia type 2 (AOA2)] and ataxia telangiectasia (OMIM 208900) in the two families. A novel homozygous missense mutation c.202 C>T (p.Arg68Cys) was identified within senataxin, SETX in the DNA of both patients in one of the families with AOA2. The patients in the second family were homozygous for a known variant in ataxia-telangiectasia mutated (ATM) gene: c.7327 C>T (p.Arg2443Ter). Both variants were absent from 100 ethnically matched control chromosomes and were either absent or present at very low frequencies in the public databases. CONCLUSIONS: This report extends the allelic heterogeneity of SETX mutations causing AOA2 and also presents an asymptomatic patient with a pathogenic ATM variant.
Subject(s)
Humans , Alleles , Apraxias , Ataxia Telangiectasia , Ataxia , Cerebellar Ataxia , DNA , Exome , Genome , Magnetic Resonance Imaging , Movement Disorders , Mutation, Missense , Neurodegenerative Diseases , Pakistan , Phenotype , Population Characteristics , Spinocerebellar Ataxias , VertebratesABSTRACT
La ataxia-telangiectasia es una entidad caracterizada por un cuadro de ataxia cerebelosa progresiva, telangiectasias, defectos inmunológicos y una mayor tendencia al desarrollo de tumores malignos. La mutación genética responsable (ataxia-telangiectasia mutada) parece jugar un papel importante en la función celular normal y el remodelado cardiovascular. Se describe la aparición de una arritmia maligna en un paciente de 14 años con un diagnóstico de ataxia-telangiectasia, en remisión completa de linfoma no Hodgkin B de alto grado. Consultó en el Servicio de Urgencias Pediátricas por episodios de presíncope, y se observó, al ingresar, bloqueo auriculoventricular completo que evolucionó hacia asistolia, por lo que requirió la colocación de un marcapasos definitivo. Las dosis acumuladas de fármacos cardiotóxicos recibidos fueron de bajo riesgo. Sin embargo, es posible que esta enfermedad degenerativa crónica afecte con el tiempo al tejido de citoconducción. En la bibliografía revisada, no existen o se desconocen reportes previos de arritmias malignas en pacientes con ataxia-telangiectasia.
Ataxia-telangiectasia is a disorder characterized by cerebellar ataxia, telangiectasia, immunodeficiency, and increased predisposition to cancer susceptibility. Mutations in the ataxia telangiectasia mutated gene seem to play an important role in normal cell function and in cardiovascular remodeling. We report a case of a 14-year-old boy with ataxia-telangiectasia and high-grade B-non-Hodgkin lymphoma who remained in continuous complete remission after chemotherapy and who was admitted into our Emergency Room presenting with episodes of presyncope. At admission he presented a complete atrioventricular block that evolved into asystole and required placement of a pacemaker. Cumulative cardiotoxic drugs received were at low risk. However, it is possible that this chronic degenerative disease may affect the cardiac conduction system over time. In the reviewed literature there are no or unknown reports of ataxia-telangiectasia with malignant cardiac arrhythmias.
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Humans , Male , Adolescent , Ataxia Telangiectasia/complications , Heart Arrest/etiology , Heart Block/etiologyABSTRACT
Introducción: El síndrome de ataxia telangiectasia (AT) es una enfermedad genética autosómica recesiva de compromiso multisistémico, con un espectro clínico amplio, ocasionada por la mutación del gen ATM, lo que causa la disminución o ausencia de la proteinkinasa ATM, por lo que se alteran procesos del ciclo celular, reparación del ADN y apoptosis. El objetivo de este artículo es el de reportar el caso de una paciente con síndrome de AT causada por una mutación no reportada previamente en la literatura. Caso clínico: Paciente originaria de Colombia, de 14 años de edad, con manifestaciones clínicas y fenotípicas clásicas del síndrome de AT a partir de los 6 años de edad, con alteración pondoestatural, infecciones respiratorias a repetición, telangiectasias oculocutáneas y compromiso neurológico progresivo, caracterizado por regresión en su desarrollo psicomotor, ataxia y apraxia oculomotora. Se realizó secuenciación del gen ATM que demostró mutación en homocigosis no reportada previamente en la literatura. Discusión: En Latinoamérica son escasos los reportes de pacientes con AT y pocos aquellos en donde se describen los hallazgos moleculares. Los estudios moleculares son una herramienta que facilita el diagnóstico y permite orientar mejor el manejo y pronóstico de pacientes con enfermedades neurodegenerativas. El reporte de variantes moleculares no descritas es de gran importancia para establecer la causa etiológica de este tipo de patologías en grupos poblacionales diversos, como lo son los países de Latinoamérica.
Introduction: The ataxia telangiectasia syndrome (AT) is a genetic disease with an autosomal recessive inheritance pattern, with multisystem involvement and a broad clinical spectrum. It is caused by the mutation of the ATM gene, causing reduction or absence of the ATM proteinkinase, altering processes in the cell cycle, DNA repair and apoptosis. The objective of this article is to report the case of a patient with ataxia telangiectasia syndrome, caused by a mutation not previously reported in the literature. Case report: A 14 year-old patient native to Colombia, with classic clinical and phenotypical manifestations of AT syndrome, which started at 6 years of age with pondostatural alteration, recurrent respiratory infections, oculocutaneus telangiectasias and progressive neurological disorder that included: regression in her psychomotor development, ataxia and oculomotor apraxia. ATM gene sequencing is performed evidencing a homozygous mutation not reported in literature. Discussion: In Latin America are sparse the number of reports of patients with ataxia telangiectasia and only few of these describe their molecular findings. Molecular studies allow the diagnosis and a better orientation in the management and prognosis of patients with neurodegenerative diseases. The report of undescribed molecular variants is of great importance to establish the etiology of such diseases in diverse population groups, such as the countries of Latin America.
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Humans , Female , Adolescent , Ataxia Telangiectasia/diagnosis , Ataxia Telangiectasia/genetics , Ataxia Telangiectasia Mutated Proteins/genetics , Mutation , Genetic MarkersABSTRACT
Objective: To investigate the effects of ataxia-telangiectasia mutated (ATM) gene-silencing on the proliferation, migration and invasion of human triple-negative breast cancer MDA-MB-231 cells. Methods: The recombinant lentiviral vectors with ATM gene-targeted specific shRNA or the negative control sequence (as the negative control group) were infected into the human triple-negative breast cancer MDA-MB-231 cells to obtain the ATM gene-silencing cells. At the same time, the uninfected MDA-MB-231 cells was used as the blank control group. After screening by puromycin, the infection efficiency of each group was observed under a fluorescence microscope. The expressions of ATM mRNA and protein in MDA-MB-231 cells in the three groups were detected by real-time fluorescent quantitative PCR and Western blotting, respectively. The effects of ATM gene-silencing on proliferation, cycle distribution, migration and invasion of MDA-MB-231 cells were analyzed by MTT method, FCM, cell wound healing assay and Transwell assays, respectively. Results: The human triple-negative breast cancer MDA-MB-231 cells with stable ATM genesilencing were established successfully. Compared with the blank control and negative control groups, the proliferation and cell cycle distribution of MDA-MB-231 cells in ATM gene-silencing group had no significant change (all P > 0.05), but the migration and invasion abilities of MDA-MB-231 cells in ATM gene-silencing group were decreased significantly (all P<0.05). Conclusion: The down-regulation of ATM gene expression can significantly inhibit the migration and invasion of human triple-negative breast cancer MDA-MB-231 cells.
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Ataxia-telangiectasia (AT) is characterized by cerebellar ataxia, progressive immunodeficiency, radiation sensitivity, telangiectasia, and predisposition to malignancy. AT patients have a 100-fold increased risk for the development of lymphoid malignancies. It is important to consider AT in a child with pre-existing ataxia, or lymphoid malignancy that was diagnosed at a younger age than expected. This consideration avoids the confusion between ataxia development and toxicity from chemotherapy. Hodgkin's lymphoma (HL) is usually treated with chemotherapy and/or radiotherapy. Unfortunately, when treated with conventional doses of radiotherapy, AT patients invariably experience devastating necrosis of their normal tissues. Therefore, a new treatment protocol for patients with HL in AT must be established. In this paper, we report the case of an 8-year-old female patient with HL in AT who was treated with chemotherapy. This patient was also treated with brentuximab (which targets CD30) for salvage therapy after the disease progressed.
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Child , Female , Humans , Ataxia , Ataxia Telangiectasia , Cerebellar Ataxia , Clinical Protocols , Drug Therapy , Hodgkin Disease , Necrosis , Radiation Tolerance , Radiotherapy , Salvage Therapy , TelangiectasisABSTRACT
Ataxia-telangiectasia (AT) is characterized by cerebellar ataxia, progressive immunodeficiency, radiation sensitivity, telangiectasia, and predisposition to malignancy. AT patients have a 100-fold increased risk for the development of lymphoid malignancies. It is important to consider AT in a child with pre-existing ataxia, or lymphoid malignancy that was diagnosed at a younger age than expected. This consideration avoids the confusion between ataxia development and toxicity from chemotherapy. Hodgkin's lymphoma (HL) is usually treated with chemotherapy and/or radiotherapy. Unfortunately, when treated with conventional doses of radiotherapy, AT patients invariably experience devastating necrosis of their normal tissues. Therefore, a new treatment protocol for patients with HL in AT must be established. In this paper, we report the case of an 8-year-old female patient with HL in AT who was treated with chemotherapy. This patient was also treated with brentuximab (which targets CD30) for salvage therapy after the disease progressed.
Subject(s)
Child , Female , Humans , Ataxia , Ataxia Telangiectasia , Cerebellar Ataxia , Clinical Protocols , Drug Therapy , Hodgkin Disease , Necrosis , Radiation Tolerance , Radiotherapy , Salvage Therapy , TelangiectasisABSTRACT
Some of the recognized actions of vitamin D include immunological effects such as keeping tolerance and to promote protective immunity. These functions are related to the blocking of B cell differentiation and immunoglobulin secretion as well as decreased production of inflammatory cytokines. The aim of this study was to describe the frequency of vitamin D deficiency in patients with primary immunodeficiencies. We studied 31 patients: 14 with Ataxia-telangiectasia (11 male, mean age 13.1±4.9 years) and 17 with Common variable immunodeficiency (8 males, mean age 28.5±11.3 years). Classification of nutritional status and percentage of fat mass were evaluated. 25-hydroxyvitamin D was analyzed by high performance liquid chromatography and deficiency was considered when 25-hydroxyvitamin D< 20 ng/mL. Malnutrition was the most common nutritional disorder: 7/14 (50%) and 4/17 (23.5%) in Ataxia-telangiectasia and Common variable immunodeficiency groups, respectively. We found a high percentage of 25-hydroxyvitamin D deficiency in the Ataxia-telangiectasia group 6/14 (42.8%) and Common variable immunodeficiency group 3/17 (17.6%). There was no association between vitamin D deficiency and high-sensitivity C-reactive protein, lymphocyte count (CD3, CD4 and CD8) and body fat percentage. Considering the frequency of autoimmune diseases and infections in patients with primary immunodeficiencies, strict monitoring of the vitamin levels are recommended with the aim to reduce morbidity.
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Presentamos el caso clínico de un niño de 9 años procedente de la región Cusco, con deterioro progresivo del estado neurológico caracterizado por síntomas cerebelosos, asociados a una historia de infecciones respiratorias repetidas y con hallazgos clínicos y de laboratorio que permitieron llegar al diagnóstico de Ataxia-Telangiectasia, enfermedad poco reportada en nuestro país. Se revisa la etiopatogenia, criterios diagnósticos y propuestas terapéuticas disponibles en la actualidad.
We report the case of a 9-year-old from the Cusco region, with progressive deterioration of neurological condition characterized by cerebellar symptoms associated with a history of repeated respiratory infections and clinical and laboratory features that allowed reaching the diagnosis of Ataxia-Telangiectasia, little reported disease in our country. The pathogenesis, diagnostic criteria and therapeutic approaches currently available are reviewed.
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Humans , Male , Child , Ataxia , Ataxia Telangiectasia , Ataxia Telangiectasia/etiologyABSTRACT
Objective To investigate the effect of silencing of ataxia-telangiectasia mutated (ATM) expression by plasmid-mediated RNA interference on the radiosensitivity of human lung adenocarcinoma A549 cells.Methods Eukaryotic expression plasmid containing ATM small interfering RNA (siRNA) (pSilencer2.1-ATM),as well as pSilencer2.1-nonspecific,was constructed.Lung adenocarcinoma A549 cells were divided into positive group,negative group,and control group to be transfected with pSilencer2.1-ATM,pSilencer2.1-nonspecific,and no plasmid,respectively.The mRNA and protein expression of ATM was measured by RT-PCR and Western blot,respectively.The change in cell radiosensitivity was observed by colony-forming assay.Cell cycle and cell apoptosis were analyzed by flow cytometry.Results The eukaryotic expression plasmid containing ATM siRNA was successfully constructed.The RT-PCR and Western blot demonstrated that the expression of ATM was down-regulated in the positive group.The sensitization enhancement ratios (D0 ratios) for the positive group and negative group were 1.50 and 1.01,respectively.The flow cytometry revealed that the proportions of A549 cells in G1 and G2/M phases were significantly lower in the positive group than in the control group (51.27％ vs 61.85％,P =0.012;6.34％ vs 10.91％,P =0.008) and that the apoptosis rate was significantly higher in the positive group than in the control group and negative group (49.31％ vs 13.58％,P=0.000;49.31％ vs 13.17％,P=0.000).Conclusions Silencing of ATM expression may increase the radiosensitivity of human lung adenocarcinoma A549 cells,probably by affecting the cell cycle and promoting cell apoptosis.
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Objective To investigate the relationship between the effect of unmethylated cytosine phosphate-guanine oligodeoxynucleotide ( CpG ODN ) 7909 on X-ray-induced G2/M phase arrest and apoptosis and the phosphorylation of ATM kinase.Methods Human lung adenocarcinoma A549 cells were randomly classified into five groups,control,CpG group,irradiation group,CpG + irradiation group and ATM siRNA + CpG + irradiation group.Cell survival fraction was evaluated by clonogenic assay.Cell cycle and apoptosis were analyzed by flow cytometry.The expressions of ATM,checkpoint kinase-2(Chk2) and p53 were detected with Western blot.Results Compared to the situation under X-ray irradiation alone,decreased cell clonogenic survival,prolonged G2/M arrest,and increased cell apoptosis were observed after the combination treatment with CpG ODN7909 and X-rays ( t =13.41,17.32 and 7.71,P ＜ 0.05).Moreover,the phosphorylations on ATM,Chk2,and p53 were increased in the irradiated A549 cells that had been pre-treated with CpG ODN7909.After ATM siRNA interfering,abrogation of G2/M arrest,reduction of apoptosis,and decrease of Chk2 and p53 phosphorylation were found in A549 cells treated with CpG ODN7909 and X-rays ( t =26.84,2.98,47.24 and 67.47,P ＜0.05).Conclusions CpG ODN7909 can enhance the X-ray-induced phosphorylation of ATM kinase in human lung adenocarcinoma cells in vitro,which might be involved in regulating G2/M phase arrest and apoptosis.
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PURPOSE: The human genetic disorder ataxia-telangiectasia (AT) is a multisystem disease characterized by extreme radiosensitivity. The recent identification of the gene mutated in AT, ATM, and the demonstration that it encodes a homologous domain of phosphatidylinositol 3-kinase (PI3-K), the catalytic subunit of an enzyme involved in transmitting signals from the cell surface to the nucleus, provide support for a role of this gene in signal transduction. Although ionizing radiation was known to induce c-fos transcription, nothing is known about how ATM or PKCI mediated signal transduction pathway modulates the c-fos gene transcription and gene expression. Here we have studied the effect of PKCI on radiation sensitivity and c-fos transcription in normal and AT cells. MATERIALS AND METHODS: Normal (LM217) and AT (AT5BIVA) cells were transfected with PKCI expression plasmid and the overexpression and integration of PKCI was evaluated by northern blotting and polymerase chain reaction, respectively. 5 Gy of radiation was exposed to LM and AT cells transfected with PKCI expression plasmid and cells were harvested 48 hours after radiation and investigated apoptosis with TUNEL method. The c-fos transcription activity was studied by performing CAT assay of reporter gene after transfection of c-fos CAT plasmid into AT and LM cells. RESULTS: Our results demonstrate for the first time a role of PKCI on the radiation sensitivity and c-fos expression in LM and AT cells. PKCI increased radiation induced apoptosis in LM cells but reduced apoptosis in AT cells. The basal c-fos transcription activity is 70 times lower in AT cells than that in LM cells. The c-fos transcription activity was repressed by overexpression of PKCI in LM cells but not in AT cells. After induction of c-fos by Ras protein, overexpression of PKCI repressed c-fos transcription in LM cells but not in AT cells CONCLUSION: Overexpression of PKCI increased radiation sensitivity and repressed c-fos transcription in LM cells but not in AT cells. The results may be a reason of increased radiation sensitivity of AT cells. PKCI may be involved in an ionizing radiation induced signal transduction pathway responsible for radiation sensitivity and c-fos transcription. The data also provided evidence for novel transcriptional difference between LM and AT cells.