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1.
BMC Med Genomics ; 15(1): 224, 2022 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-36316743

RESUMO

BACKGROUND: To date, only twenty-one cases diagnosed postnatally with mosaic trisomy 12 have been reported. The most frequent phenotypic manifestations are developmental delay, dysmorphic facial features, congenital heart defects, digital alterations, and pigmentary disorders. In the present report, detailed clinical and genetic profiles of three unrelated new patients with mosaic trisomy 12 are described and compared with previously reported cases. CASE PRESENTATION: In the present report, we include the clinical, cytogenetic, and molecular description of three Mexican patients diagnosed postnatally with mosaic trisomy 12. At phenotypic level, the three patients present with developmental delay, dysmorphic facial features, congenital heart defects and skin pigmentary anomalies. Particularly, patient 1 showed unique eye alterations as bilateral distichiasis, triple rows of upper lashes, and digital abnormalities. In patient 2 redundant skin, severe hearing loss, and hypotonia were observed, and patient 3 presented with hypertelorism and telecanthus. Hyperpigmentation with disseminated pigmentary anomalies is a common trait in all of them. The cytogenetic study was carried out under the strict criteria of analysis, screening 50-100 metaphases from three different tissues, showing trisomy 12 mosaicism in at least one of the three different tissues analyzed. With SNParray, the presence of low-level mosaic copy number variants not previously detected by cytogenetics, and uniparental disomy of chromosome 12, was excluded. STR markers allowed to confirm the absence of uniparental disomy as well as to know the parental origin of supernumerary chromosome 12. CONCLUSIONS: The detailed clinical, cytogenetic, and molecular description of these three new patients, contributes with relevant information to delineate more accurately a group of patients that show a heterogeneous phenotype, although sharing the same chromosomal alteration. The possibility of detecting mosaic trisomy 12 is directly associated with the sensitivity of the methodology applied to reveal the low-level chromosomal mosaicism, as well as with the possibility to perform the analysis in a suitable tissue.


Assuntos
Transtornos Cromossômicos , Trissomia , Humanos , Trissomia/genética , Mosaicismo , Dissomia Uniparental/diagnóstico , Dissomia Uniparental/genética , Transtornos Cromossômicos/genética , Análise Citogenética
2.
Hum Exp Toxicol ; 38(8): 951-961, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31018701

RESUMO

The transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) is a master regulator of a battery of antioxidant and detoxificant genes with cytoprotective function. Since Nrf2 inactivation is necessary for the complete execution of apoptosis in the presence of extensive cellular damage caused by oxidative stress, constant activation of Nrf2 may protect tumoral cells from apoptosis. The tumor suppressor gene p53 has been suggested to participate in apoptosis-related repression of Nrf2. Thus, we studied the inactivation of Nrf2 during oxidant-induced apoptosis in a p53 dysfunctional cellular model. Using curcumin dose-response assay and time-response assay in an immortalized lymphoblastoid cell line (control line 45), we observed a time-dependent increase in apoptotic markers such as deoxyribonucleic acid (DNA) fragmentation, phosphatidylserine exposure, and caspase-3, caspase-9 and poly (ADP-ribose) polymerases (PARP) cleavage. Interestingly, at early times of exposure to a proapoptotic dose of curcumin (15 µM), we observed nuclear accumulation of Nrf2 and the expression of Nrf2 target genes, whereas at late exposure times we found a reduction of total and nuclear protein levels of Nrf2 as well as downregulation of Nrf2 target genes in the absence of p53 activation. These data suggest that apoptosis-related inactivation of Nrf2 could occur in a p53 dysfunctional background, opening the possible occurrence of p53-independent mechanism to explain Nrf2 inactivation during apoptosis.


Assuntos
Apoptose/efeitos dos fármacos , Curcumina/farmacologia , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Humanos , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismo
3.
Hum Exp Toxicol ; 33(6): 582-9, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24107458

RESUMO

Inorganic arsenic (iAs) is an important pollutant associated with various chronic-degenerative diseases. The cytoprotective protein nuclear factor erythroid 2-related factor (NRF2) has been proposed as an important responsive mechanism against iAs exposure. The aim of this study was to determine whether the risk of skin lesions in people exposed to iAs-contaminated water could be modified by the presence of single nucleotide polymorphisms in the NRF2 coding gene. We studied 117 individuals with long-term iAs exposure and 120 nonexposed individuals. Total As was determined in water, meanwhile iAs and its metabolites were measured in urine. The iAs-induced skin lesion status was evaluated by expert dermatologists. We sequenced the promoter region of NRF2 in a sample of 120 healthy donors. We found four polymorphisms previously reported and one novel polymorphism in the 5' regulatory region of the NRF2. In this study, we did not find allelic and genotype association of NRF2 polymorphisms with iAs-related skin lesion. However, the analysis of haplotypes composed by -653GA, and -617CA NRF2 single nucleotide polymorphisms showed a significant association with protection against skin lesions in the low-As exposure group. This is the first report studying the association between NRF2 polymorphisms and susceptibility of As-related skin lesions. Increasing the sample size will allow us to confirm this data.


Assuntos
Intoxicação por Arsênico/genética , Arsênio/efeitos adversos , Fator 2 Relacionado a NF-E2/genética , Polimorfismo de Nucleotídeo Único , Dermatopatias/induzido quimicamente , Dermatopatias/genética , Poluentes Químicos da Água/efeitos adversos , Adolescente , Adulto , Intoxicação por Arsênico/diagnóstico , Intoxicação por Arsênico/prevenção & controle , Estudos de Casos e Controles , Estudos Transversais , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Regiões Promotoras Genéticas , Fatores de Proteção , Fatores de Risco , Dermatopatias/diagnóstico , Dermatopatias/prevenção & controle , Adulto Jovem
4.
Lupus ; 19(10): 1237-42, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20507872

RESUMO

Systemic lupus erythematosus (SLE) is an autoimmune disease associated with oxidative stress and characterized by chronic inflammation. Kidney malfunction, an aggressive characteristic of this disease, is not present in all affected individuals. The Nrf2-Keap1 pathway is important in protecting against oxidative stress and inflammation. Mouse models and genome-wide scans have suggested NRF2 (Nuclear factor (erythroid-derived 2)-like 2) as a candidate gene for susceptibility to SLE. We therefore investigated whether NRF2 polymorphisms are associated with childhood-onset SLE in a Mexican Mestizo population. Two single nucleotide polymorphisms (SNPs) were genotyped by TaqMan((R)) assays in 362 patients with childhood-onset SLE and 379 controls. We found no significant association between susceptibility to SLE and NRF2 polymorphisms. However, after population stratification by gender, the heterozygous genotype of the -653G/A SNP was significantly associated with nephritis in females only [OR = 1.81, CI (1.04-3.12), p = 0.032]. This association was stronger in females affected with severe nephritis [classes IV-VI; OR = 2.16, CI (1.12-4.15), p = 0.019]. Our results suggest that NRF2 is not associated with susceptibility to childhood-onset SLE, but it could confer a risk for developing kidney malfunction in SLE-affected individuals.


Assuntos
Lúpus Eritematoso Sistêmico/genética , Nefrite Lúpica/genética , Fator 2 Relacionado a NF-E2/genética , Idade de Início , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Lúpus Eritematoso Sistêmico/fisiopatologia , Masculino , México/epidemiologia , Polimorfismo de Nucleotídeo Único , Índice de Gravidade de Doença , Fatores Sexuais
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