Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 32
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Hum Mutat ; 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31730716

RESUMO

Hypertrophic cardiomyopathy (HCM) is the most common heritable cardiomyopathy, historically believed to affect 1 of 500 people. MYBPC3 pathogenic variations are the most frequent cause of familial HCM and more than 90% of them introduce a premature termination codon. The current study aims to determine the prevalence of deep intronic MYBPC3 pathogenic variations that could lead to splice mutations. To improve molecular diagnosis, a next-generation sequencing (NGS) workflow based on whole MYBPC3 sequencing of a cohort of 93 HCM patients, for whom no putatively causative point mutations were identified after NGS sequencing of a panel of 48 cardiomyopathy-causing genes, was performed. Our approach led us to reconsider the molecular diagnosis of six patients of the cohort (6.5%). These HCM probands were carriers of either a new large MYBPC3 rearrangement or splice intronic variations (five cases). Four pathogenic intronic variations, including three novel ones, were detected. Among them, the prevalence of one of them (NM_000256.3:c.1927+ 600 C>T) was estimated at about 0.35% by the screening of 1,040 unrelated HCM individuals. This study suggests that deep MYBPC3 splice mutations account for a significant proportion of HCM cases (6.5% of this cohort). Consequently, NGS sequencing of MYBPC3 intronic sequences have to be performed systematically.

2.
Toxicol Appl Pharmacol ; 381: 114712, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31437493

RESUMO

Stringent toxicological tests have to be performed prior to the industrial development of alternative chemicals particularly high energy dense materials (HEDMs) such as explosives. The properties (e.g., power, stability) of these compounds are constantly being improved, the current axis of research being the nitration of nitrogen heterocycles leading to HEDMs such as nitropyrazole-derived molecules. However, except for 3,4,5-trinitropyrazole (3,4,5-TNP), which was shown to be highly toxic in mice, the toxicological impact of these HEDMs has so far not been investigated. Furthermore, as industrials are strongly advised to develop alternative safety testing assays to in vivo experiments, we herein focused on determining the cytotoxic and genotoxic effects of seven Nitropyrazole-derived HEDMs on three rodent cell lines (mouse embryonic BALB/3T3 clone A31 cells, Chinese hamster ovary cells CHO-K1 and mouse lymphoma L5178Y TK +/- clone (3.7.2C) cells), two human fibroblast lines (CRC05, PFS04062) and on the human hepatic HepaRG model (both in proliferative and differentiated cells). A stronger cytotoxic effect was observed for 1,3-dinitropyrazole (1, 3-DNP) and 3,4,5-TNP in all cell lines, though differentiated HepaRG cells clearly displayed fewer likely due to the metabolism and elimination of these molecules by their functional biotransformation pathways. At the mechanistic level, the sub-chronic cytotoxic and genotoxic effects were linked to ROS/RNS production (experimental assays), HA2.X and to transcriptomic data highlighting the increase in DNA repair mechanisms.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31310703

RESUMO

Pros and cons of crossover design are well known for estimating the treatment effect compared to parallel-group design, but remain unclear for identifying and estimating an interaction between a potential biomarker and the treatment effect. Such 'predictive' biomarkers, or 'effect modifiers', help to predict the response to specific treatments. The purpose of this report was to better characterize the advantages and disadvantages of crossover versus parallel-group design to identify predictive biomarkers. The treatment effect, the effect of a binary biomarker and their interaction were modelled using a linear model. The intra-subject correlation in the crossover design was taken into account through an intra-class correlation coefficient. The variance-covariance matrix of the parameters was derived and compared. For both trial designs, the variance of the parameter estimating an interaction between the treatment effect and a potential predictive biomarker corresponds to the variance of the parameter estimating the treatment effect, multiplied by the inverse of the frequency of the candidate biomarker. The ratio of the variance of the interaction parameter in the crossover to the variance estimated in the parallel-group design depends on the complement of the intra-class correlation coefficient. When planning a clinical trial including a search for candidate biomarker, the frequency of the candidate biomarker helps design the sample size, and the intra-subject correlation of the outcome should be taken into account for choosing between parallel-group and crossover designs.

4.
Hum Mutat ; 40(11): 1993-2000, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31230393

RESUMO

Human retrocopies, that is messenger RNA transcripts benefitting from the long interspersed element 1 machinery for retrotransposition, may have specific consequences for genomic testing. Next genetration sequencing (NGS) techniques allow the detection of such mobile elements but they may be misinterpreted as genomic duplications or be totally overlooked. We report eight observations of retrocopies detected during diagnostic NGS analyses of targeted gene panels, exome, or genome sequencing. For seven cases, while an exons-only copy number gain was called, read alignment inspection revealed a depth of coverage shift at every exon-intron junction where indels were also systematically called. Moreover, aberrant chimeric read pairs spanned entire introns or were paired with another locus for terminal exons. The 8th retrocopy was present in the reference genome and thus showed a normal NGS profile. We emphasize the existence of retrocopies and strategies to accurately detect them at a glance during genetic testing and discuss pitfalls for genetic testing.

7.
J Med Genet ; 56(8): 526-535, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30923172

RESUMO

BACKGROUND: Balanced chromosomal rearrangements associated with abnormal phenotype are rare events, but may be challenging for genetic counselling, since molecular characterisation of breakpoints is not performed routinely. We used next-generation sequencing to characterise breakpoints of balanced chromosomal rearrangements at the molecular level in patients with intellectual disability and/or congenital anomalies. METHODS: Breakpoints were characterised by a paired-end low depth whole genome sequencing (WGS) strategy and validated by Sanger sequencing. Expression study of disrupted and neighbouring genes was performed by RT-qPCR from blood or lymphoblastoid cell line RNA. RESULTS: Among the 55 patients included (41 reciprocal translocations, 4 inversions, 2 insertions and 8 complex chromosomal rearrangements), we were able to detect 89% of chromosomal rearrangements (49/55). Molecular signatures at the breakpoints suggested that DNA breaks arose randomly and that there was no major influence of repeated elements. Non-homologous end-joining appeared as the main mechanism of repair (55% of rearrangements). A diagnosis could be established in 22/49 patients (44.8%), 15 by gene disruption (KANSL1, FOXP1, SPRED1, TLK2, MBD5, DMD, AUTS2, MEIS2, MEF2C, NRXN1, NFIX, SYNGAP1, GHR, ZMIZ1) and 7 by position effect (DLX5, MEF2C, BCL11B, SATB2, ZMIZ1). In addition, 16 new candidate genes were identified. Systematic gene expression studies further supported these results. We also showed the contribution of topologically associated domain maps to WGS data interpretation. CONCLUSION: Paired-end WGS is a valid strategy and may be used for structural variation characterisation in a clinical setting.

8.
Toxicol Appl Pharmacol ; 355: 103-111, 2018 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-29959026

RESUMO

The high-energy compound 3,4,5-trinitropyrazole (TNP) was developed as an alternative to other less energetic and more sensitive explosive materials, in particular 1-methyl-2,4,6-trinitrobenzene (TNT). However, the level of toxicity of TNP remains understudied. Here using an in vivo CD1 mouse model, we mimicked an acute exposure (24 h) to TNP, given either orally or intravenously, and determined the maximum administrable doses (190 mg/kg and 11 mg/kg, respectively), as well as the lethal dose for 50% (LD50) of female or male mice (390 mg/kg for both) treated intravenously with TNP alone. Several metabolites including nitroso-dinitro-pyrazole, hydroxylamino-dinitro-pyrazole, hydroxyl-dinitro-pyrazole and amino-dinitro-pyrazole were identified in urine. TNP is quickly metabolized and eliminated via urine as two main amino-dinitro-pyrazole metabolites. A comparison of the transcriptomic effects of TNP and TNT after 10 days exposure enabled us to demonstrate no major induction of transcripts involved both in cell death mechanisms (apoptosis, necrosis, autophagy) and physiological pathways (glycolysis, ATP production). Finally, subchronic exposure to TNP was replicated in female mice, fed 16.8-52.8 mg/kg/day of TNP for one month, to study the impact on cellular functions. Although blood TNP levels remained high, a lower rate of TNP accumulation in the liver and lungs were observed than during an acute exposure. Conversely, cellular stress functions explored using the RT2 Profiler™ PCR Array Mouse Molecular Toxicology PathwayFinder remained unaltered after this chronic exposure. These findings demonstrate that TNP can be rapidly eliminated in vivo without accumulating in vital organs.

9.
Oncotarget ; 9(30): 21122-21131, 2018 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-29765524

RESUMO

CfDNA samples from colon (mCRC) and non-small cell lung cancers (NSCLC) (CIRCAN cohort) were compared using three platforms: droplet digital PCR (ddPCR, Biorad); BEAMing/OncoBEAM™-RAS-CRC (Sysmex Inostics); next-generation sequencing (NGS, Illumina), utilizing the 56G oncology panel (Swift Biosciences). Tissue biopsy and time matched cfDNA samples were collected at diagnosis in the mCRC cohort and during 1st progression in the NSCLC cohort. Excellent matches between cfDNA/FFPE mutation profiles were observed. Detection thresholds were between 0.5-1% for cfDNA samples examined using ddPCR and NGS, and 0.03% with BEAMing. This high level of sensitivity enabled the detection of KRAS mutations in 5/19 CRC patients with negative FFPE profiles. In the mCRC cohort, comparison of mutation results obtained by testing FFPE to those obtained by testing cfDNA by ddPCR resulted in 47% sensitivity, 77% specificity, 70% positive predictive value (PPV) and 55% negative predictive value (NPV). For BEAMing, we observed 93% sensitivity, 69% specificity, 78% PPV and 90% NPV. Finally, sensitivity of NGS was 73%, specificity was 77%, PPV 79% and NPV 71%. Our study highlights the complementarity of different diagnostic approaches and variability of results between OncoBEAM™-RAS-CRC and NGS assays. While the NGS assay provided a larger breadth of coverage of the major targetable alterations of 56 genes in one run, its performance for specific alterations was frequently confirmed by ddPCR results.

10.
Int J Mol Sci ; 19(4)2018 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-29677173

RESUMO

High throughput sequencing (HTS) is increasingly important in determining cancer diagnoses, with subsequent prognostic and therapeutic implications. The biology of cancer is becoming increasingly deciphered and it is clear that therapy needs to be individually tailored. Whilst translational research plays an important role in lymphoid malignancies, few guidelines exist to guide biologists and routine laboratories through this constantly evolving field. In this article, we review the challenges of interpreting HTS in lymphoid malignancies and provide a toolkit to interpret single nucleotide variants obtained from HTS. We define the pre-analytical issues such as sequencing DNA obtained from formalin-fixed and paraffin-embedded tissue (FFPE), the acquisition of germline DNA, or the bioinformatic pitfalls, the analytical issues encountered and how to manage them. We describe the main constitutional and cancer databases, their characteristics and limitations, with an emphasis on variant interpretation in lymphoid malignancies. Finally, we discuss the challenges of predictions that one can make using in silico or in vitro modelling, pharmacogenomic screening, and the limits of those prediction tools. This description of the current status in genomic interpretation highlights the need for new large databases and international collaboration in the lymphoma field.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala/métodos , Mutação/genética , Biologia Computacional , Formaldeído/química , Humanos , Linfoma/genética , Inclusão em Parafina , Análise de Sequência de DNA , Fixação de Tecidos
11.
Ann Neurol ; 83(5): 926-934, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29630738

RESUMO

OBJECTIVE: Cut homeodomain transcription factor CUX2 plays an important role in dendrite branching, spine development, and synapse formation in layer II to III neurons of the cerebral cortex. We identify a recurrent de novo CUX2 p.Glu590Lys as a novel genetic cause for developmental and epileptic encephalopathy (DEE). METHODS: The de novo p.Glu590Lys variant was identified by whole-exome sequencing (n = 5) or targeted gene panel (n = 4). We performed electroclinical and imaging phenotyping on all patients. RESULTS: The cohort comprised 7 males and 2 females. Mean age at study was 13 years (0.5-21.0). Median age at seizure onset was 6 months (2 months to 9 years). Seizure types at onset were myoclonic, atypical absence with myoclonic components, and focal seizures. Epileptiform activity on electroencephalogram was seen in 8 cases: generalized polyspike-wave (6) or multifocal discharges (2). Seizures were drug resistant in 7 or controlled with valproate (2). Six patients had a DEE: myoclonic DEE (3), Lennox-Gastaut syndrome (2), and West syndrome (1). Two had a static encephalopathy and genetic generalized epilepsy, including absence epilepsy in 1. One infant had multifocal epilepsy. Eight had severe cognitive impairment, with autistic features in 6. The p.Glu590Lys variant affects a highly conserved glutamine residue in the CUT domain predicted to interfere with CUX2 binding to DNA targets during neuronal development. INTERPRETATION: Patients with CUX2 p.Glu590Lys display a distinctive phenotypic spectrum, which is predominantly generalized epilepsy, with infantile-onset myoclonic DEE at the severe end and generalized epilepsy with severe static developmental encephalopathy at the milder end of the spectrum. Ann Neurol 2018;83:926-934.

12.
BMC Med Genomics ; 11(1): 23, 2018 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-29510755

RESUMO

BACKGROUND: Sarcoidosis (OMIM 181000) is a multi-systemic granulomatous disorder of unknown origin. Despite multiple genome-wide association (GWAS) studies, no major pathogenic pathways have been identified to date. To find out relevant sarcoidosis predisposing genes, we searched for de novo and recessive mutations in 3 young probands with sarcoidosis and their healthy parents using a whole-exome sequencing (WES) methodology. METHODS: From the SARCFAM project based on a national network collecting familial cases of sarcoidosis, we selected three families (trios) in which a child, despite healthy parents, develop the disease before age 15 yr. Each trio was genotyped by WES (Illumina HiSEQ 2500) and we selected the gene variants segregating as 1) new mutations only occurring in affected children and 2) as recessive traits transmitted from each parents. The identified coding variants were compared between the three families. Allelic frequencies and in silico functional results were analyzed using ExAC, SIFT and Polyphenv2 databases. The clinical and genetic studies were registered by the ClinicalTrials.gov - Protocol Registration and Results System (PRS) ( https://clinicaltrials.gov ) receipt under the reference NCT02829853 and has been approved by the ethical committee (CPP LYON SUD EST - 2 - REF IRB 00009118 - September 21, 2016). RESULTS: We identified 37 genes sharing coding variants occurring either as recessive mutations in at least 2 trios or de novo mutations in one of the three affected children. The genes were classified according to their potential roles in immunity related pathways: 9 to autophagy and intracellular trafficking, 6 to G-proteins regulation, 4 to T-cell activation, 4 to cell cycle and immune synapse, 2 to innate immunity. Ten of the 37 genes were studied in a bibliographic way to evaluate the functional link with sarcoidosis. CONCLUSIONS: Whole exome analysis of case-parent trios is useful for the identification of genes predisposing to complex genetic diseases as sarcoidosis. Our data identified 37 genes that could be putatively linked to a pediatric form of sarcoidosis in three trios. Our in-depth focus on 10 of these 37 genes may suggest that the formation of the characteristic lesion in sarcoidosis, granuloma, results from combined deficits in autophagy and intracellular trafficking (ex: Sec16A, AP5B1 and RREB1), G-proteins regulation (ex: OBSCN, CTTND2 and DNAH11), T-cell activation (ex: IDO2, IGSF3), mitosis and/or immune synapse (ex: SPICE1 and KNL1). The significance of these findings needs to be confirmed by functional tests on selected gene variants.

13.
Genes Chromosomes Cancer ; 57(6): 320-328, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29460398

RESUMO

Reliable interpretation of comparative genomic hybridization array (aCGH) results requires centralization and normalization of the data. We evaluated the reliability of aCGH centralization by comparing aCGH results (with classical centralization-normalization steps) to fluorescence in situ hybridization (FISH) results. In addition, we propose a method to correct centralization bias. Sixty-six pituitary tumors were analyzed (Agilent aCGH + SNP 4 × 180K microarray). For each tumor, the FISH-based log2 (ratios) of a subset of chromosomes were compared with the corresponding aCGH raw log2 (ratios). With our new normalization-centralization process, this difference was added to all log2 (ratios), before performing loess regression on non-altered probes only. Finally, the mean log2 (ratio) and the percentage of normal probes were compared between CGHnormaliter and our new FISH-based method. For 11 tumors, FISH results and raw CGH log2 (ratios) differed significantly. In addition, nine tumors showed discrepancies between results generated by CGHnormaliter and our new-method. Such discrepancies seemed to occur with tumours with many abnormalities (0%-40% normal probes), rather than in those tumours with fewer abnormalities (31%-100% normal probes). Five tumors had too few normal probes to allow normalization. In these tumors, which can exhibit many changes in DNA copy number, we found that centralization bias was frequent and uncorrected by current normalization methods. Therefore, an external control for centralization, such as FISH analysis, is required to insure reliable interpretation of aCGH data.


Assuntos
Hibridização Genômica Comparativa/métodos , Neoplasias Hipofisárias/genética , Adulto , Idoso , Pré-Escolar , Cromossomos Humanos , Variações do Número de Cópias de DNA , Feminino , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Adulto Jovem
14.
Cell Mol Life Sci ; 75(1): 67-79, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28864883

RESUMO

Transcriptional regulation of proteins involved in neuronal polarity is a key process that underlies the ability of neurons to transfer information in the central nervous system. The Collapsin Response Mediator Protein (CRMP) family is best known for its role in neurite outgrowth regulation conducting to neuronal polarity and axonal guidance, including CRMP5 that drives dendrite differentiation. Although CRMP5 is able to control dendritic development, the regulation of its expression remains poorly understood. Here we identify a Sox5 consensus binding sequence in the putative promoter sequence upstream of the CRMP5 gene. By luciferase assays we show that Sox5 increases CRMP5 promoter activity, but not if the putative Sox5 binding site is mutated. We demonstrate that Sox5 can physically bind to the CRMP5 promoter DNA in gel mobility shift and chromatin immunoprecipitation assays. Using a combination of real-time RT-PCR and quantitative immunocytochemistry, we provide further evidence for a Sox5-dependent upregulation of CRMP5 transcription and protein expression in N1E115 cells: a commonly used cell line model for neuronal differentiation. Furthermore, we report that increasing Sox5 levels in this neuronal cell line inhibits neurite outgrowth. This inhibition requires CRMP5 because CRMP5 knockdown prevents the Sox5-dependent effect. We confirm the physiological relevance of the Sox5-CRMP5 pathway in the regulation of neurite outgrowth using mouse primary hippocampal neurons. These findings identify Sox5 as a critical modulator of neurite outgrowth through the selective activation of CRMP5 expression.


Assuntos
Amidoidrolases/genética , Regulação da Expressão Gênica , Crescimento Neuronal/genética , Fatores de Transcrição SOXD/genética , Amidoidrolases/metabolismo , Animais , Sítios de Ligação/genética , Encéfalo/embriologia , Encéfalo/metabolismo , Linhagem Celular Tumoral , Humanos , Camundongos , Mutação , Neuritos/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Regiões Promotoras Genéticas/genética , Ligação Proteica , Fatores de Transcrição SOXD/metabolismo
15.
Artigo em Inglês | MEDLINE | ID: mdl-28781888

RESUMO

Uveal melanoma, a rare malignant tumor of the eye, is predominantly observed in populations of European ancestry. A genome-wide association study of 259 uveal melanoma patients compared to 401 controls all of European ancestry revealed a candidate locus at chromosome 5p15.33 (region rs421284: OR = 1.7, CI 1.43-2.05). This locus was replicated in an independent set of 276 cases and 184 controls. In addition, risk variants from this region were positively associated with higher expression of CLPTM1L. In conclusion, the CLPTM1L region contains risk alleles for uveal melanoma susceptibility, suggesting that CLPTM1L could play a role in uveal melanoma oncogenesis.

16.
PLoS One ; 12(3): e0173022, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28282386

RESUMO

Cystic fibrosis (CF) lungs harbor a complex community of interacting microbes, including pathogens like Pseudomonas aeruginosa. Meta-taxogenomic analysis based on V5-V6 rrs PCR products of 52 P. aeruginosa-positive (Pp) and 52 P. aeruginosa-negative (Pn) pooled DNA extracts from CF sputa suggested positive associations between P. aeruginosa and Stenotrophomonas and Prevotella, but negative ones with Haemophilus, Neisseria and Burkholderia. Internal Transcribed Spacer analyses (RISA) from individual DNA extracts identified three significant genetic structures within the CF cohorts, and indicated an impact of P. aeruginosa. RISA clusters Ip and IIIp contained CF sputa with a P. aeruginosa prevalence above 93%, and of 24.2% in cluster IIp. Clusters Ip and IIIp showed lower RISA genetic diversity and richness than IIp. Highly similar cluster IIp RISA profiles were obtained from two patients harboring isolates of a same P. aeruginosa clone, suggesting convergent evolution in the structure of their microbiota. CF patients of cluster IIp had received significantly less antibiotics than patients of clusters Ip and IIIp but harbored the most resistant P. aeruginosa strains. Patients of cluster IIIp were older than those of Ip. The effects of P. aeruginosa on the RISA structures could not be fully dissociated from the above two confounding factors but several trends in these datasets support the conclusion of a strong incidence of P. aeruginosa on the genetic structure of CF lung microbiota.


Assuntos
Bactérias/genética , Fibrose Cística/complicações , DNA Bacteriano/metabolismo , Infecções por Pseudomonas/complicações , Escarro/microbiologia , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Bactérias/isolamento & purificação , Análise por Conglomerados , Fibrose Cística/diagnóstico , DNA Bacteriano/genética , Eletroforese em Gel de Campo Pulsado , Variação Genética , Humanos , Incidência , Metagenômica , Testes de Sensibilidade Microbiana , Microbiota , Reação em Cadeia da Polimerase , Infecções por Pseudomonas/epidemiologia , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/genética , Pseudomonas aeruginosa/isolamento & purificação , RNA Ribossômico/genética , RNA Ribossômico/metabolismo , RNA Ribossômico 16S/genética , RNA Ribossômico 16S/metabolismo
17.
Orphanet J Rare Dis ; 11(1): 165, 2016 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-27914482

RESUMO

BACKGROUND: The occurrence of familial forms of sarcoidosis (OMIM 181100) suggests a genetic predisposition. The involvement of butyrophilin-like 2 (BTNL2) gene (rs2076530 variant) has to be investigated. RESULTS: The study performed independent analyses of BTNL2 polymorphism, clinical phenotypes, and outcomes in familial vs. sporadic presentations in 256 sporadic and 207 familial cases from 140 families. The logistic multivariate model showed that a young age at diagnosis and the combination of lung and skin involvement at diagnosis may distinguish sporadic from familial sarcoidosis (p = 0.016 and p = 0.041). We observed also that Sarcoid Clinical Activity Classification (SCAC) profiles were significantly different between familial and sporadic cases (p = 0.0497). Variant rs2076530 was more frequent in patients than in controls (OR = 2.02; 95% CI: [1.32-3.09]) but showed no difference between sporadic and familial cases and no difference according to the clinical phenotype or the outcome. CONCLUSION: Despite a significant difference in BTNL2 polymorphism between sarcoid patients and controls, there was no such difference between familial and sporadic sarcoidosis cases and no correlation between BTNL2 polymorphism and disease severity or outcome. Thus, BTNL2 difference cannot be considered as a key marker for disease classification or patient management.


Assuntos
Butirofilinas/genética , Polimorfismo de Nucleotídeo Único/genética , Sarcoidose/genética , Sarcoidose/patologia , Adulto , Feminino , Predisposição Genética para Doença/genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada
18.
Neurol Neuroimmunol Neuroinflamm ; 2(6): e166, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26568967

RESUMO

OBJECTIVE: To evaluate the presence of immunoglobulin A (IgA) subtype of anti-NMDA receptor (NMDAR) antibodies (IgA-NMDAR-Abs) in the CSF of patients with immunoglobulin G (IgG)-NMDAR-Ab encephalitis and to describe the potential association with a specific clinical pattern. METHODS: The retrospective analysis for the presence of IgA-NMDAR-Abs in 94 CSF samples from patients with anti-NMDAR encephalitis diagnosed between October 2007 and February 2014 was conducted at the French Reference Centre on Paraneoplastic Neurological Syndrome. This observational study compared 39 patients with both IgA- and IgG-NMDAR-Abs to 55 patients with only IgG-NMDAR-Abs. RESULTS: In the retrospective cohort, 41% of the patients with NMDAR-Ab encephalitis had both CSF IgG- and IgA-NMDAR-Abs. Approximately half of the IgA-NMDAR-Ab-positive patients (18/38, 49%) definitively possessed associated tumors, primarily ovarian teratomas (17/18, 94%), compared with only 5% (3/55) of the patients in the IgA-NMDAR-Ab-negative group (p < 0.001). In the adult female population at risk for ovarian teratoma, the detection of CSF IgA-NMDAR-Ab positivity showed 85% sensitivity, 70% specificity, a 57% positive predictive value, and a 90% negative predictive value for the diagnosis of ovarian teratoma. No other specific clinical features or clinical outcome were associated with CSF IgA-NMDAR-Ab positivity. CONCLUSION: These results suggest that in patients with IgG-NMDAR-Ab encephalitis, CSF IgA-NMDAR-Abs could be used as a biological marker for the presence of an ovarian teratoma.

19.
Breast Cancer Res ; 17: 61, 2015 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-25925750

RESUMO

INTRODUCTION: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. METHODS: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. RESULTS: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. CONCLUSIONS: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.


Assuntos
Neoplasias da Mama/genética , Genes BRCA2 , Genes Mitocondriais , Heterozigoto , Mutação , Proteína BRCA1/genética , Feminino , Predisposição Genética para Doença , Haplótipos , Humanos , Filogenia , Risco
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA