Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.746
Filtrar
1.
Artigo em Russo | MEDLINE | ID: mdl-31407689

RESUMO

The authors present an unique familial case of ataxia-telangiectasia (AT) mimicking autosomal dominant inheritance with different phenotypes in a 3-year-old boy (ataxia and moderate dyskinesia since 1.5 years) and his 31-year-old mother (mild dystonia, predominantly torticollis, since 10 years). Exome sequencing of the boy detected two heterozygous ATM mutations c.1564_1565delGA (p.Glu522fs) and c.6154G>A (p.Glu2052Lys) reported earlier. Sanger sequencing found both mutations in the child, the father was heterozygous for c.1564_1565delGA, the mother for 6154G>A earlier reported in the rare A-T phenotype of 'pure' local dystonia. Exome sequencing of the mother, who considered herself healthy, detected the allelic ATM mutation c.7630-2A>C in intron 51.


Assuntos
Ataxia Telangiectasia , Distúrbios Distônicos , Ataxia Telangiectasia/complicações , Ataxia Telangiectasia/genética , Criança , Pré-Escolar , Heterozigoto , Humanos , Masculino , Linhagem , Fenótipo
2.
Int J Radiat Oncol Biol Phys ; 105(4): 698-712, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31381960

RESUMO

The advent of affordable and rapid next-generation DNA sequencing technology, along with the US Supreme Court ruling invalidating gene patents, has led to a deluge of germline and tumor genetic variant tests that are being rapidly incorporated into clinical cancer decision-making. A major concern for clinicians is whether the presence of germline mutations may increase the risk of radiation toxicity or secondary malignancies. Because scarce clinical data exist to inform decisions at this time, the American Society for Radiation Oncology convened a group of radiation science experts and clinicians to summarize potential issues, review relevant data, and provide guidance for adult patients and their care teams regarding the impact, if any, that genetic testing should have on radiation therapy recommendations. During the American Society for Radiation Oncology workshop, several main points emerged, which are discussed in this manuscript: (1) variants of uncertain significance should be considered nondeleterious until functional genomic data emerge to demonstrate otherwise; (2) possession of germline alterations in a single copy of a gene critical for radiation damage responses does not necessarily equate to increased risk of radiation-induced toxicity; (3) deleterious ataxia-telangiesctasia gene mutations may modestly increase second cancer risk after radiation therapy, and thus follow-up for these patients after indicated radiation therapy should include second cancer screening; (4) conveying to patients the difference between relative and absolute risk is critical to decision-making; and (5) more work is needed to assess the impact of tumor somatic alterations on the probability of response to radiation therapy and the potential for individualization of radiation doses. Data on radiosensitivity related to specific genetic mutations is also briefly discussed.


Assuntos
Testes Genéticos , Mutação , Neoplasias/genética , Neoplasias/radioterapia , Radio-Oncologistas , Tolerância a Radiação/genética , Adulto , Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/genética , Tomada de Decisão Clínica , Consenso , Reparo do DNA/genética , Genes BRCA1 , Genes BRCA2 , Variação Genética , Mutação em Linhagem Germinativa , Pesquisas sobre Serviços de Saúde , Heterozigoto , Humanos , Neoplasias Induzidas por Radiação/genética , Segunda Neoplasia Primária/genética , Síndrome , Terminologia como Assunto
3.
Mol Med Rep ; 20(2): 1655-1662, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31257506

RESUMO

Ataxia­telangiectasia (A­T) syndrome is a rare autosomal recessive disorder mainly caused by mutations in the A­T mutated (ATM) gene. However, the genomic abnormalities and their consequences associated with the pathogenesis of A­T syndrome remain to be fully elucidated. In the present study, a whole­exome sequencing analysis of a family with A­T syndrome was performed, revealing a novel homozygous deletion mutation [namely, NM_000051.3:c.50_72+7del,p.Asp18_Lys24delins(23)] in ATM in three affected siblings, which was inherited from their carrier parents who exhibited a normal phenotype in this pedigree. The identified mutation spans the exon 2 and intron 2 regions of the ATM gene, causing a splicing aberration that resulted in a 30­bp deletion in exon 2 and intron 2, as well as a 71­bp insertion in intron 2 in the splicing process, which was confirmed by reverse transcription­polymerase chain reaction and sequencing analysis. The change in the three­dimensional structure of the protein caused by the mutation in ATM may affect the functions associated with telomere length maintenance and DNA damage repair. Taken together, the present study reported a novel homozygous deletion mutation in the ATM gene resulting in A­T syndrome in a Chinese pedigree and expanded on the spectrum of known causative mutations of the ATM gene.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Ataxia Telangiectasia/genética , Deleção de Sequência , Grupo com Ancestrais do Continente Asiático/genética , Criança , Análise Mutacional de DNA , Feminino , Homozigoto , Humanos , Masculino , Modelos Moleculares , Linhagem , Sequenciamento Completo do Exoma
4.
PLoS One ; 14(5): e0216668, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31107893

RESUMO

Oxidative stress has been shown to play a crucial role in the pathophysiology of the neurodegenerative disease Ataxia Telangiectasia. We have recently demonstrated that Dexamethasone treatment is able to counteract the oxidative state by promoting nuclear factor erythroid 2-related factor 2 (NRF2) nuclear accumulation. However, substantial gaps remain in our knowledge of the underlying molecular mechanism(s) according to which Dexamethasone acts as an NRF2 inducer. Herein we investigate the possible effects of the drug on the main NRF2 activation pathways by initially focusing on key kinases known to differently affect NRF2 activation. Neither AKT nor ERK1/2, known to be NRF2-activating kinases, were found to be activated upon Dexamethasone treatment, thus excluding their involvement in the transcription factor nuclear shift. Likewise, GSK3 inactivating kinase was not inhibited, thus ruling out its role in NRF2 activation. On the other hand, p38 MAPK, another NRF2-inhibitory kinase, was indeed switched-off in Ataxia Telangiectasia cells by Dexamethasone-mediated induction of DUSP1 phosphatase, and therefore it appeared that it might account for NRF2 triggering. However, this mechanism was excluded by the use of a selective p38 inhibitor, which failed to cause a significant NRF2 nuclear shift and target gene induction. Finally, dexamethasone effects on the classical oxidative pathway orchestrated by KEAP1 were addressed. Dexamethasone was found to decrease the expression of the inhibitor KEAP1 at both mRNA and protein levels and to induce the shift from the reduced to the oxidized form of KEAP1, thus favouring NRF2 translocation into the nucleus. Furthermore, preliminary data revealed very low levels of the negative regulator Fyn in Ataxia Telangiectasia cells, which might account for the prolonged NRF2-activated gene expression.


Assuntos
Ataxia Telangiectasia/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Antioxidantes/metabolismo , Ataxia Telangiectasia/genética , Linhagem Celular , Dexametasona/farmacologia , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/antagonistas & inibidores , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Fator 2 Relacionado a NF-E2/genética , Doenças Neurodegenerativas/genética , Oxirredução , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/fisiologia
5.
J Exp Clin Cancer Res ; 38(1): 149, 2019 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-30961670

RESUMO

BACKGROUND: The cisplatin-resistance is still a main course for chemotherapy failure of lung cancer patients. Cisplatin-resistant cancer cells own higher malignance and exhibited increased metastatic ability, but the mechanism is not clear. In this study, we investigated the effects of Ataxia Telangiectasia Mutated (ATM) on lung cancer metastasis. MATERIALS AND METHODS: Cisplatin-resistant A549CisR and H157CisR cell line were generated by long-term treating parental A549 and H157 cells (A549P and H157P) with cisplatin. Cell growth, cell migration and cell invasion were determined. Gene expressions were determined by Western Blot and qPCR. Tumor metastasis was investigated using a xenograft mouse model. RESULTS: The IC50 of the cisplatin-resistant cells (A549CisR and H157CisR cells) to cisplatin was 6-8 higher than parental cells. The A549CisR and H157CisR cells expressed lower level of E-cadherin and higher levels of N-cadherin, Vimentin and Snail compared to the parental A549P and H157P cells, and exhibited stronger capabilities of metastatic potential compared to the parental cells. The ATM expression was upregulated in A549CisR and H157CisR cells and cisplatin treatment also upregulated expression of ATM in parental cells, The inhibition of ATM by using specific ATM inhibitor CP466722 or knock-down ATM by siRNA suppressed Epithelial-to-Mesenchymal transition (EMT) and metastatic potential of A549CisR and H157CisR cells. These data suggest that ATM mediates the cisplatin-resistance in lung cancer cells. Expressions of JAK1,2,、 STAT3 、PD-L1 and ATM were increased in A549CisR and H157CisR cells and could by induced by cisplatin in parental lung cancer cells. Interestedly, ATM upregulated PD-L1 expression via JAK1,2/STAT3 pathway and inhibition of ATM decreased JAK/STAT3 signaling and decreased PD-L1 expression. The treatment of PD-L1 neutralizing Ab reduced EMT and cell invasion. Inhibition of JAK1,2/STAT3 signaling by specific inhibitors suppressed ATM-induced PD-L1 expression, EMT and cell invasion. Importantly, inhibition of ATM suppressed EMT and tumor metastasis in cisplatin-resistant lung cancer cells in an orthotopic xenograft mouse model. CONCLUSIONS: Our results show that ATM regulates PD-L1 expression through activation of JAK/STAT3 signaling in cisplatin-resistant cells. Overexpression of ATM contributes to cisplatin-resistance in lung cancer cells. Inhibition of ATM reversed EMT and inhibited cell invasion and tumor metastasis. Thus, ATM may be a potential target for the treatment of cisplatin-resistant lung cancer.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Ataxia Telangiectasia/genética , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Neoplasias Pulmonares/genética , Fator de Transcrição STAT3/metabolismo , Animais , Ataxia Telangiectasia/patologia , Humanos , Neoplasias Pulmonares/patologia , Camundongos , Metástase Neoplásica
6.
Mol Med Rep ; 19(5): 3441-3448, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30816533

RESUMO

Ataxia­telangiectasia (A­T) is an autosomal recessive chromosome breakage disorder caused by mutations in the ATM serine/threonine kinase (ATM) gene. Typically, it presents in early childhood with progressive cerebellar dysfunction, accompanied by immunodeficiency and oculocutaneous telangiectasia. In the present study, the clinical and genetic findings of a Chinese family affected with A­T in two live siblings, the proband (II­2) and his elder brother (II­1), as well as a fetus (II­3) were reported. General health, clinical neurological, electrophysiological (motor and sensory nerve conduction) and magnetic resonance imaging evaluations revealed that patients II­1 and II­2 had similar symptoms of ataxia, dysarthria, conjunctival hyperemia and elevated serum α­fetoprotein, whereas patient II­1 had earlier A­T onset at 2 years old and more serious problems with movement and intelligence. Targeted sequencing followed by Sanger sequencing revealed that these two patients carried the compound heterozygotes of a novel nonsense mutation c.5170G>T (p.Glu1724Ter) and a known nonsense mutation c.748C>T (p.Arg250Ter) in the ATM gene. Each mutation was inherited from an asymptomatic parent, which therefore confirmed the diagnosis of A­T. Given this, proband's mother performed prenatal diagnosis in her third pregnancy. Unfortunately, the fetus had the same causal mutations as its siblings and the pregnancy was terminated. The findings of the present study expanded the mutation spectrum of the ATM gene and may help in understanding the genetic basis of A­T, in order to guide genetic counseling and prenatal diagnosis.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Ataxia Telangiectasia/diagnóstico , Ataxia Telangiectasia/genética , Estudos de Associação Genética , Aconselhamento Genético , Mutação , Fenótipo , Alelos , Grupo com Ancestrais do Continente Asiático , Ataxia Telangiectasia/fisiopatologia , Biomarcadores , Cerebelo/patologia , Biologia Computacional , Análise Mutacional de DNA , Eletromiografia , Feminino , Genótipo , Humanos , Imagem por Ressonância Magnética , Masculino , Linhagem , Avaliação de Sintomas
7.
Clin Immunol ; 200: 55-63, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30639167

RESUMO

Ataxia-Telangiectasia (AT) is an immunodeficiency most often associated with T cell abnormalities. We describe a patient with a hyper-IgM phenotype and immune cell abnormalities that suggest a distinct clinical phenotype. Significant B cell abnormalities with increased unswitched memory B cells, decreased naive transitional B cells, and an elevated frequency of CD19+CD38loCD27-CD10-CD21-/low B cells expressing high levels of T-bet and Fas were demonstrated. The B cells were hyporesponsive to in vitro stimulation through the B cell receptor, Toll like receptors (TLR) 7 and 9, and CD40. T cell homeostasis was also disturbed with a significant increase in γδ T cells, circulating T follicular helper cells (Tfh), and decreased numbers of T regulatory cells. The ATM mutations in this patient are posited to have resulted in the perturbations in the frequencies and distributions of B and T cell subsets, resulting in the phenotype in this patient. KEY MESSAGES: A novel mutation creating a premature stop codon and a nonsense mutation in the ATM gene are postulated to have resulted in the unique clinical picture characterized by abnormal B and T cell populations, lymphocyte subset dysfunction, granuloma formation, and a hyper-IgM phenotype. CAPSULE SUMMARY: A patient presented with ataxia-telangiectasia, cutaneous granulomas, and a hyper-IgM phenotype; a novel combination of mutations in the ATM gene was associated with abnormal distributions, frequencies, and function of T and B lymphocyte subsets.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Ataxia Telangiectasia/genética , Subpopulações de Linfócitos B/imunologia , Granuloma/genética , Síndrome de Imunodeficiência com Hiper-IgM/genética , Dermatopatias/genética , Subpopulações de Linfócitos T/imunologia , Ataxia Telangiectasia/imunologia , Linfócitos B/imunologia , Pré-Escolar , Códon sem Sentido , Feminino , Granuloma/imunologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Síndrome de Imunodeficiência com Hiper-IgM/imunologia , Memória Imunológica , Análise de Sequência de DNA , Dermatopatias/imunologia , Linfócitos T/imunologia
8.
J Clin Immunol ; 39(1): 81-89, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30607663

RESUMO

The association of immunodeficiency-related vaccine-derived rubella virus (iVDRV) with cutaneous and visceral granulomatous disease has been reported in patients with primary immunodeficiency disorders (PIDs). The majority of these PID patients with rubella-positive granulomas had DNA repair disorders. To support this line of inquiry, we provide additional descriptive data on seven previously reported patients with Nijmegen breakage syndrome (NBS) (n = 3) and ataxia telangiectasia (AT) (n = 4) as well as eight previously unreported patients with iVDRV-induced cutaneous granulomas and DNA repair disorders including NBS (n = 1), AT (n = 5), DNA ligase 4 deficiency (n = 1), and Artemis deficiency (n = 1). We also provide descriptive data on several previously unreported PID patients with iVDRV-induced cutaneous granulomas including cartilage hair hypoplasia (n = 1), warts, hypogammaglobulinemia, immunodeficiency, myelokathexis (WHIM) syndrome (n = 1), MHC class II deficiency (n = 1), Coronin-1A deficiency (n = 1), X-linked severe combined immunodeficiency (X-SCID) (n = 1), and combined immunodeficiency without a molecular diagnosis (n = 1). At the time of this report, the median age of the patients with skin granulomas and DNA repair disorders was 9 years (range 3-18). Cutaneous granulomas have been documented in all, while visceral granulomas were observed in six cases (40%). All patients had received rubella virus vaccine. The median duration of time elapsed from vaccination to the development of cutaneous granulomas was 48 months (range 2-152). Hematopoietic cell transplantation was reported to result in scarring resolution of cutaneous granulomas in two patients with NBS, one patient with AT, one patient with Artemis deficiency, one patient with DNA Ligase 4 deficiency, one patient with MHC class II deficiency, and one patient with combined immunodeficiency without a known molecular etiology. Of the previously reported and unreported cases, the majority share the diagnosis of a DNA repair disorder. Analysis of additional patients with this complication may clarify determinants of rubella pathogenesis, identify specific immune defects resulting in chronic infection, and may lead to defect-specific therapies.


Assuntos
Reparo do DNA/genética , Granuloma/complicações , Granuloma/virologia , Síndromes de Imunodeficiência/complicações , Vírus da Rubéola/patogenicidade , Dermatopatias/etiologia , Dermatopatias/virologia , Adolescente , Ataxia Telangiectasia/genética , Ataxia Telangiectasia/virologia , Criança , Pré-Escolar , Feminino , Granuloma/genética , Cabelo/anormalidades , Cabelo/virologia , Transplante de Células-Tronco Hematopoéticas/métodos , Doença de Hirschsprung/genética , Doença de Hirschsprung/virologia , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/virologia , Masculino , Síndrome de Quebra de Nijmegen/genética , Síndrome de Quebra de Nijmegen/virologia , Osteocondrodisplasias/congênito , Osteocondrodisplasias/genética , Osteocondrodisplasias/virologia , Rubéola (Sarampo Alemão)/genética , Rubéola (Sarampo Alemão)/virologia , Pele/virologia , Dermatopatias/genética , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/genética , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/virologia
9.
Pediatr Allergy Immunol ; 30(3): 277-288, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30685876

RESUMO

Ataxia-telangiectasia (A-T) is an autosomal recessive primary immunodeficiency (PID) disease that is caused by mutations in ataxia-telangiectasia mutated (ATM) gene encoding a serine/threonine protein kinase. A-T patients represent a broad range of clinical manifestations including progressive cerebellar ataxia, oculocutaneous telangiectasia, variable immunodeficiency, radiosensitivity, susceptibility to malignancies, and increased metabolic diseases. This congenital disorder has phenotypic heterogeneity, and the severity of symptoms varies in different patients based on severity of mutations and disease progression. The principal role of nuclear ATM is the coordination of cellular signaling pathways in response to DNA double-strand breaks, oxidative stress, and cell cycle checkpoint. The pathogenesis of A-T is not limited to the role of ATM in the DNA damage response (DDR) pathway, and it has other functions mainly in the hematopoietic cells and neurons. ATM adjusts the functions of organelles such as mitochondria and peroxisomes and also regulates angiogenesis and glucose metabolisms. However, ATM has other functions in the cells (especially cell viability) that need further investigations. In this review, we described functions of ATM in the nucleus and cytoplasm, and also its association with some disorder formation such as neurologic, immunologic, vascular, pulmonary, metabolic, and dermatologic complications.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Ataxia Telangiectasia/diagnóstico , Ataxia Telangiectasia/complicações , Ataxia Telangiectasia/genética , Diagnóstico Diferencial , Humanos , Mutação , Patologia Molecular
10.
Ann Neurol ; 85(2): 170-180, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30549301

RESUMO

OBJECTIVE: Variant ataxia-telangiectasia is caused by mutations that allow some retained ataxia telangiectasia-mutated (ATM) kinase activity. Here, we describe the clinical features of the largest established cohort of individuals with variant ataxia-telangiectasia and explore genotype-phenotype correlations. METHODS: Cross-sectional data were collected retrospectively. Patients were classified as variant ataxia-telangiectasia based on retained ATM kinase activity. RESULTS: The study includes 57 individuals. Mean age at assessment was 37.5 years. Most had their first symptoms by age 10 (81%). There was a diagnostic delay of more than 10 years in 68% and more than 20 years in one third of probands. Disease severity was mild in one third of patients, and 43% were still ambulant 20 years after disease onset. Only one third had predominant ataxia, and 18% had a pure extrapyramidal presentation. Individuals with extrapyramidal presentations had milder neurological disease severity. There were no significant respiratory or immunological complications, but 25% of individuals had a history of malignancy. Missense mutations were associated with milder neurological disease severity, but with a higher risk of malignancy, compared to leaky splice site mutations. INTERPRETATION: Individuals with variant ataxia-telangiectasia require malignancy surveillance and tailored management. However, our data suggest the condition may sometimes be mis- or underdiagnosed because of atypical features, including exclusive extrapyramidal symptoms, normal eye movements, and normal alpha-fetoprotein levels in some individuals. Missense mutations are associated with milder neurological presentations, but a particularly high malignancy risk, and it is important for clinicians to be aware of these phenotypes. ANN NEUROL 2019;85:170-180.


Assuntos
Ataxia Telangiectasia/diagnóstico , Ataxia Telangiectasia/genética , Doenças dos Gânglios da Base/diagnóstico , Doenças dos Gânglios da Base/genética , Genótipo , Índice de Gravidade de Doença , Adolescente , Adulto , Criança , Estudos de Coortes , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto/genética , Estudos Retrospectivos , Adulto Jovem
11.
Neurology ; 92(1): e19-e29, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30504431

RESUMO

OBJECTIVE: To describe and classify the neurologic trajectories in patients with mild neurologic forms of ataxia telangiectasia (A-T) from the Dutch A-T cohort, combined with patients reported in the literature. METHODS: Clinical, genetic, and laboratory data of 14 patients with mild neurologic phenotypes of A-T from the Dutch cohort were analyzed and combined with corresponding data from the literature. A mild neurologic phenotype was defined by a later onset, nonataxia presenting or dominant feature, or slower progression compared to the classic A-T phenotype. Neurologic trajectories were classified based on age at onset, presenting feature, and follow-up data. RESULTS: One hundred five patients were included in the study. Neurologic trajectories were categorized into 6 groups: patients with childhood-onset extrapyramidal (EP) features with cerebellar symptoms developing later (group 1; 18 patients), childhood-onset cerebellar symptoms, with EP features developing later (group 2; 35 patients), childhood- to adolescence-onset dystonia, without cerebellar symptoms (group 3; 23 patients), childhood- to adolescence-onset isolated cerebellar symptoms (group 4; 22 patients), childhood- to adult-onset prominent muscle weakness (group 5; 2 patients), and patients with adult-onset EP features, with anterior horn cell disease arising subsequently (group 6; 5 patients). CONCLUSIONS: This systematic study of the different motor abnormalities and their course over time in patients with mild phenotypes of A-T, enabled us to recognize 6 essentially different phenotypic patterns. Awareness of these different trajectories of motor abnormalities in milder forms of A-T will contribute to a reduction of diagnostic delay in this severe multisystem disorder.


Assuntos
Ataxia Telangiectasia/complicações , Ataxia Telangiectasia/diagnóstico , Transtornos dos Movimentos/etiologia , Adulto , Idade de Início , Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/genética , Estudos de Coortes , Bases de Dados Bibliográficas/estatística & dados numéricos , Feminino , Humanos , Masculino , Mutação/genética , Fenótipo
12.
Cerebellum ; 18(2): 225-244, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30338439

RESUMO

Ataxia-telangiectasia (AT) is an autosomal recessive, multisystem disease causing cerebellar ataxia, mucocutaneous telangiectasias, immunodeficiency, and malignancies. A pilot study reported cognitive and behavioral manifestations characteristic of the cerebellar cognitive affective / Schmahmann syndrome (CCAS). We set out to test and further define these observations because a more comprehensive understanding of the spectrum of impairments in AT is essential for optimal management. Twenty patients (12 males; 9.86 ± 5.5 years, range 4.3 to 23.2) were grouped by age: AT-I (toddlers and preschoolers, n = 7, 4.3-5.9 years), AT-II (school children, n = 7, 5.9-9.8 years), AT-III (adolescents/young adults, n = 6, 12.6-23.2 years). Standard and experimental tests investigated executive, linguistic, visual-spatial, and affective/social-cognitive domains. Results were compared to standard norms and healthy controls. Cognitive changes in AT-I were limited to mild visual-spatial disorganization. Spatial deficits were greater in AT-II, with low average scores on executive function (auditory working memory), expressive language (vocabulary), academic abilities (math, spelling, reading), social cognition (affect recognition from faces), and emotional/psychological processing. Full Scale IQ scores were low average to borderline impaired. AT-III patients had the greatest level of deficits which were evident particularly in spatial skills, executive function (auditory working memory, sequencing, word/color interference, set-shifting, categorization errors, perseveration), academic achievement, social cognition (affect recognition from faces), and behavioral control. Full Scale IQ scores in this group fell in the impaired range, while language was borderline impaired for comprehension, and low average for expression. Cognitive deficits in AT at a young age are mild and limited to visual-spatial functions. More widespread cognitive difficulties emerge with age and disease progression, impacting executive function, spatial skills, affect, and social cognition. Linguistic processing remains mildly affected. Recognition of the CCAS in children with AT may facilitate therapeutic interventions to improve quality of life.


Assuntos
Afeto , Ataxia Telangiectasia/psicologia , Disfunção Cognitiva , Adolescente , Ataxia Telangiectasia/genética , Criança , Pré-Escolar , Cognição , Disfunção Cognitiva/genética , Estudos de Coortes , Feminino , Estudos de Associação Genética , Humanos , Masculino , Testes Neuropsicológicos , Qualidade de Vida , Síndrome , Adulto Jovem
13.
J Pediatr Hematol Oncol ; 41(3): 243-246, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30339652

RESUMO

A unique consanguineous family with 2 genomic instability disorders, Fanconi anemia and ataxia telangiectasia, revealed exceptional combinations of null mutations in the FANCA and ATM genes. Two siblings with Fanconi anemia had novel homozygous consecutive microdeletions (c.1361-1370delCCTCCTTTGG, c.1374delC) adjoined to upstream 65 nucleotide direct tandem repeats and deletion hotspot motifs in the FANCA gene. The sibling with ataxia telangiectasia revealed a homozygous p.Arg2993Stop (c.8977C>T) null mutation in the ATM gene. All patients were also heterozygous for the opposite mutations without any additional clinical or laboratory manifestations. Double heterozygote parents did not present any clinical symptoms suggestive of the 2 disorders.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Ataxia Telangiectasia/genética , Proteína do Grupo de Complementação A da Anemia de Fanconi/genética , Anemia de Fanconi/genética , Feminino , Heterozigoto , Homozigoto , Humanos , Masculino , Deleção de Sequência , Irmãos
14.
Brain Dev ; 41(2): 150-157, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30301590

RESUMO

OBJECTIVES: Defects in DNA damage responses or repair mechanisms cause numerous rare inherited diseases, referred to as "DNA-repair defects" or "DNA damage deficiency", characterized by neurodegeneration, immunodeficiency, and/or cancer predisposition. Early accurate diagnosis is important for informing appropriate clinical management; however, diagnosis is frequently challenging and can be delayed, due to phenotypic heterogeneity. Comprehensive genomic analysis could overcome this disadvantage. The objectives of this study were to determine the prevalence of ataxia-telangiectasia (A-T) and A-T-like DNA-repair defects in Japan and to determine the utility of comprehensive genetic testing of presumptively diagnosed patients in facilitating early diagnosis. METHODS: A nationwide survey of diseases presumably caused by DNA-repair defects, including A-T, was performed. Additionally, comprehensive next-generation sequencing (NGS) analysis, targeting known disease-causing genes, was conducted. RESULTS: Sixty-three patients with A-T or other diseases with characteristics of DNA-repair defects were identified. Thirty-four patients were genetically or clinically definitively diagnosed with A-T (n = 22) or other DNA-repair defects (n = 12). Genetic analysis of 17 presumptively diagnosed patients revealed one case of ataxia with oculomotor apraxia type 1 (AOA1); one ataxia with oculomotor apraxia type 2 (AOA2); two types of autosomal dominant spinocerebellar ataxia (SCA5, SCA29); two CACNA1A-related ataxias; one microcephaly with or without chorioretinopathy, lymphedema, or mental retardation (MCLMR); and one autosomal dominant KIF1A-related disorder with intellectual deficit, cerebellar atrophy, spastic paraparesis, and optic nerve atrophy. The diagnostic yield was 58.8%. CONCLUSION: Comprehensive genetic analysis of targeted known disease-causing genes by NGS is a powerful diagnostic tool for subjects with indistinguishable neurological phenotypes resembling DNA-repair defects.


Assuntos
Ataxia Telangiectasia/epidemiologia , Ataxia Telangiectasia/genética , Distúrbios no Reparo do DNA/epidemiologia , Distúrbios no Reparo do DNA/genética , Adolescente , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Ataxia Telangiectasia/diagnóstico , Criança , Pré-Escolar , Distúrbios no Reparo do DNA/diagnóstico , Diagnóstico Precoce , Feminino , Predisposição Genética para Doença , Testes Genéticos , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Adulto Jovem
15.
Front Immunol ; 9: 2703, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30515174

RESUMO

Ataxia-telangiectasia (A-T) is a complex disease arising from mutations in the ATM gene (Ataxia-Telangiectasia Mutated), which plays crucial roles in repairing double-strand DNA breaks (DSBs). Heterogeneous immunodeficiency, extreme radiosensitivity, frequent appearance of tumors and neurological degeneration are hallmarks of the disease, which carries high morbidity and mortality because only palliative treatments are currently available. Gene therapy was effective in animal models of the disease, but the large size of the ATM cDNA required the use of HSV-1 or HSV/AAV hybrid amplicon vectors, whose characteristics make them unlikely tools for treating A-T patients. Due to recent advances in vector packaging, production and biosafety, we developed a lentiviral vector containing the ATM cDNA and tested whether or not it could rescue cellular defects of A-T human mutant fibroblasts. Although the cargo capacity of lentiviral vectors is an inherent limitation in their use, and despite the large size of the transgene, we successfully transduced around 20% of ATM-mutant cells. ATM expression and phosphorylation assays indicated that the neoprotein was functional in transduced cells, further reinforced by their restored capacity to phosphorylate direct ATM substrates such as p53 and their capability to repair radiation-induced DSBs. In addition, transduced cells also restored cellular radiosensitivity and cell cycle abnormalities. Our results demonstrate that lentiviral vectors can be used to rescue the intrinsic cellular defects of ATM-mutant cells, which represent, in spite of their limitations, a proof-of-concept for A-T gene therapy.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia , Ataxia Telangiectasia , Fibroblastos , Vetores Genéticos , Lentivirus , Mutação , Transdução Genética , Ataxia Telangiectasia/genética , Ataxia Telangiectasia/metabolismo , Ataxia Telangiectasia/patologia , Proteínas Mutadas de Ataxia Telangiectasia/biossíntese , Proteínas Mutadas de Ataxia Telangiectasia/genética , Linhagem Celular , Fibroblastos/metabolismo , Fibroblastos/patologia
16.
PLoS One ; 13(12): e0209496, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30586396

RESUMO

INTRODUCTION: Classic ataxia telangiectasia (A-T) is an autosomal recessive disease characterized by early onset ataxia, immune deficiency, sino-pulmonary disease, lymphoid/solid malignancies and telangiectasias. Prior studies have suggested that chronic inflammation and premature aging may contribute to the development of malignancy and pulmonary disease in people with A-T. To further examine the link between A-T and inflammation, we hypothesized that subjects with classic A-T would have greater enrichment of inflammatory pathways in peripheral blood mononuclear cells (PBMCs) compared to non A-T age-matched controls. To test this hypothesis we used RNAseq as an unsupervised approach to identify biological processes altered in people with classic A-T. METHODS: PBMCs were isolated from subjects with classic A-T and compared to non-A-T age-matched healthy controls. RNAseq with differential gene expression analyses was then performed. Selected genes were validated by RT-qPCR using cohorts of subjects consisting of classic A-T, mild A-T or non-A-T controls. Subjects with mild A-T were characterized by later onset/mild neurologic features and normal/near normal immune status. RESULTS: RNAseq revealed 310 differentially expressed genes (DEGs) including genes involved in inflammation, immune regulation, and cancer. Using gene set enrichment analysis, A-T subjects were found to have biological processes enriched for inflammatory and malignancy pathways. In examining a cohort of A-T subjects in which baseline serum IL8 and IL6 levels were measured previously, an association was found between higher serum IL8 levels and higher likelihood of developing malignancy and/or death in a subsequent 4-6 year period. CONCLUSION: RNAseq using PBMCs from subjects with classic A-T uncovered differential expression of immune response genes and biological processes associated with inflammation, immune regulation, and cancer. Follow-up of A-T subjects over a 4-6 year period revealed an association between higher baseline serum IL8 levels and malignancy/death. These findings support a role for inflammation as a contributing factor in A-T phenotypes.


Assuntos
Ataxia Telangiectasia/sangue , Regulação da Expressão Gênica/imunologia , Inflamação/sangue , Leucócitos Mononucleares/metabolismo , Neoplasias/epidemiologia , Adolescente , Adulto , Ataxia Telangiectasia/genética , Ataxia Telangiectasia/imunologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Seguimentos , Perfilação da Expressão Gênica , Voluntários Saudáveis , Humanos , Inflamação/genética , Inflamação/imunologia , Interleucina-8/genética , Interleucina-8/imunologia , Interleucina-8/metabolismo , Leucócitos Mononucleares/imunologia , Masculino , Neoplasias/sangue , Neoplasias/genética , Neoplasias/imunologia , Fenótipo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sequência de RNA , Adulto Jovem
17.
Mutat Res Genet Toxicol Environ Mutagen ; 836(Pt A): 117-123, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30389154

RESUMO

The ataxia telangiectasia mutated (ATM) protein is a pivotal multifunctional protein kinase predominantly involved in DNA damage response, as well as in maintaining overall functional integrity of the cells. Apart from playing its major role in regulating the cellular response to DNA damage, ATM, when mutated, can additionally determine oxidative stress, metabolic syndrome, mitochondrial dysfunction and neurodegeneration. In the present paper we aim to investigate the levels of oxidative stress potentially induced by the oxidizing rodent renal carcinogen KBrO3 in ATM-defective lymphoblastoid cell lines (LCLs) established from four classical AT patients (with different ATM mutations), one AT variant with reduced hypersensitivity to X rays, obligate AT heterozygotes and wild type intrafamilial control. A possible modulatory involvement of PARP in potentially induced oxidative stress is also evaluated following its inhibition with 3-aminobenzamide (3-AB). Treatments with KBrO3 clearly showed a marked hypersensitivity of the ATM-defective LCLs, including the AT variant. A marked and statistically significant reduction of KBrO3-induced chromosomal damage following inhibition of PARP by 3-AB, was observed in all AT LCLs, but not in those from the AT variant, AT heterozygotes and wild type intrafamilial control. This result is suggestive of a modulatory involvement of PARP in the hypersensitivity of ATM-defective cells to DNA oxidative damage.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/deficiência , Bromatos/farmacologia , Dano ao DNA , Hipersensibilidade/tratamento farmacológico , Linfócitos/patologia , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Ataxia Telangiectasia/tratamento farmacológico , Ataxia Telangiectasia/enzimologia , Ataxia Telangiectasia/genética , Ataxia Telangiectasia/patologia , Células Cultivadas , Reparo do DNA , Humanos , Hipersensibilidade/genética , Hipersensibilidade/metabolismo , Hipersensibilidade/patologia , Linfócitos/efeitos dos fármacos , Linfócitos/efeitos da radiação , Estresse Oxidativo , Fosforilação
18.
Mutat Res Genet Toxicol Environ Mutagen ; 836(Pt B): 122-126, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30442337

RESUMO

Ataxi A-T elangiectasia (AT) is a multisystem, complex and rare disease inherited in an autosomal recessive manner. Homozygous individuals have a variety of pathological manifestations, however, heterozygotes only present a higher risk of developing cancer. We evaluated the background levels of DNA damage (basal damage) and cell response to bleomycin or ionizing radiation using Comet assay and the cytokinesis-block micronucleus (CBMN) test in individuals with AT, their parents and controls. To evaluate DNA repair, the challenge experiment with ionizing radiation was performed using Comet assay, and different recovery times were evaluated. Results showed that basal MN frequencies differ between patients, parents and controls. Meanwhile, using the Comet assay, the results from the basal analysis do not differ between the groups, but monitoring the kinetics of DNA repair, we verified that the group of patients showed a delay in repair, compared to controls. Another finding was the nuclear bud (NBUD) frequency: spontaneous and induced cell cultures (with bleomycin and radiation) showed clear differences between patients, parents and controls. The CBMN assay and repair measurement with the Comet assay can help in the diagnosis of AT patients and ATM gene carriers, as complementary methods. The use of genomic instability evaluation techniques for the identification of the heterozygotes in families, where at least one member is affected, may be of great clinical importance.


Assuntos
Ataxia Telangiectasia/diagnóstico , Ataxia Telangiectasia/genética , Ensaio Cometa/métodos , Dano ao DNA , Reparo do DNA , Testes para Micronúcleos/métodos , Adolescente , Adulto , Proteínas Mutadas de Ataxia Telangiectasia/genética , Estudos de Casos e Controles , Feminino , Instabilidade Genômica , Heterozigoto , Humanos , Masculino , Mutação , Pais
19.
Neurogenetics ; 19(4): 237-255, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30343341

RESUMO

Autosomal recessive ataxia telangiectasia (A-T) is characterized by radiosensitivity, immunodeficiency, and cerebellar neurodegeneration. A-T is caused by inactivating mutations in the ataxia telangiectasiamutated (ATM) gene, a serine-threonine protein kinase involved in DNA damage response and excitatory neurotransmission. The selective vulnerability of cerebellar Purkinje neurons (PN) to A-T is not well understood. Employing global proteomic profiling of cerebrospinal fluid from patients at ages around 15 years, we detected reduced calbindin, reelin, cerebellin-1, cerebellin-3, protocadherin fat 2, sempahorin 7A, and increased apolipoprotein B and J peptides. Bioinformatic enrichment was observed for pathways of lipoproteins, endocytosis, extracellular matrix receptor interaction, peptidase activity, adhesion, calcium binding, and complement immunity. This seemed important since secretion of reelin from glutamatergic afferent axons is crucial for PN lipoprotein receptor endocytosis and lipid signaling. Reelin expression is downregulated by irradiation and reelin/ApoB mutations are known causes of ataxia. Validation efforts in 2-month-old Atm-/- mice before onset of motor deficits confirmed cerebellar transcript reductions for reelin receptors Apoer2/Vldlr with increases for their ligands Apoe/Apoh and cholesterol 24-hydroxylase Cyp46a1. Concomitant dysregulations were found for Vglut2/Sema7a as climbing fiber markers, glutamate receptors like Grin2b, and calcium homeostasis factors (Atp2b2, Calb1, Itpr1), while factors involved in DNA damage, oxidative stress, neuroinflammation, and cell adhesion were normal at this stage. Quantitative immunoblots confirmed ApoB and ApoJ increases and VLDLR reduction in cerebellar tissue at the age of 2 months. These findings show that ApoB excess and reelin signaling deficits reflect the neurodegeneration in A-T in a sensitive and specific way. As extracellular factors, apolipoproteins and their cargo such as vitamin E may be useful for neuroprotective interventions.


Assuntos
Apolipoproteínas B , Ataxia Telangiectasia/genética , Ataxia Telangiectasia/metabolismo , Moléculas de Adesão Celular Neuronais , Proteínas da Matriz Extracelular , Proteínas do Tecido Nervoso , Serina Endopeptidases , Adolescente , Animais , Apolipoproteínas B/genética , Apolipoproteínas B/metabolismo , Ataxia Telangiectasia/patologia , Proteínas Mutadas de Ataxia Telangiectasia/genética , Estudos de Casos e Controles , Moléculas de Adesão Celular Neuronais/genética , Moléculas de Adesão Celular Neuronais/metabolismo , Criança , Pré-Escolar , Modelos Animais de Doenças , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Camundongos , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Transdução de Sinais/genética
20.
DNA Repair (Amst) ; 72: 10-17, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30348496

RESUMO

The genome instability syndrome, ataxia-telangiectasia (A-T) is caused by null mutations in the ATM gene, that lead to complete loss or inactivation of the gene's product, the ATM protein kinase. ATM is the primary mobilizer of the cellular response to DNA double-strand breaks (DSBs) - a broad signaling network in which many components are ATM targets. The major clinical feature of A-T is cerebellar atrophy, characterized by relentless loss of Purkinje and granule cells. In Atm-knockout (Atm-KO) mice, complete loss of Atm leads to a very mild neurological phenotype, suggesting that Atm loss is not sufficient to markedly abrogate cerebellar structure and function in this organism. Expression of inactive ("kinase-dead") Atm (AtmKD) in mice leads to embryonic lethality, raising the question of whether conditional expression of AtmKD in the murine nervous system would lead to a more pronounced neurological phenotype than Atm loss. We generated two mouse strains in which AtmKD was conditionally expressed as the sole Atm species: one in the CNS and one specifically in Purkinje cells. Focusing our analysis on Purkinje cells, the dynamics of DSB readouts indicated that DSB repair was delayed longer in the presence of AtmKD compared to Atm loss. However, both strains exhibited normal life span and displayed no gross cerebellar histological abnormalities or significant neurological phenotype. We conclude that the presence of AtmKD is indeed more harmful to DSB repair than Atm loss, but the murine central nervous system can reasonably tolerate the extent of this DSB repair impairment. Greater pressure needs to be exerted on genome stability to obtain a mouse model that recapitulates the severe A-T neurological phenotype.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/deficiência , Proteínas Mutadas de Ataxia Telangiectasia/genética , Ataxia Telangiectasia/genética , Cerebelo/metabolismo , Quebras de DNA de Cadeia Dupla , Reparo do DNA/genética , Fenótipo , Animais , Ataxia Telangiectasia/patologia , Cerebelo/patologia , Regulação da Expressão Gênica , Técnicas de Inativação de Genes , Camundongos , Células de Purkinje/patologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA